Clozapine in Practice: Counseling Strategies and Evolving Safety Considerations

In this Pharmacy Times Q&A with Jonathan Leung, PharmD, RPh, BCPS, a clinical pharmacist specialist in pharmacotherapy and psychiatry at Mayo Clinic in Rochester, Minnesota, he discusses best practices for counseling patients on clozapine, emphasizing early education and individualized, ongoing support to address hesitations around monitoring and adverse effects. He highlights evolving evidence suggesting reduced long-term risk of neutropenia and discusses international shifts toward less intensive absolute neutrophil count (ANC) monitoring, alongside the need for shared decision-making in clinical practice.

Pharmacy Times: What are your best practices for counseling patients on the risks and benefits of clozapine—especially those hesitant about blood monitoring or adverse effects?

Jonathan Leung, PharmD, RPh, BCPS: First, I think it is important to broach the concept of clozapine as early as possible. Patients should be at least familiar with the name clozapine by the time it is indicated. This is analogous to introducing long-acting injectable antipsychotics early in treatment, even though many clinicians may consider these agents only after adherence concerns with oral medication arise.

Admittedly, there is a lot to cover with clozapine, and it can be overwhelming, making educational interventions challenging at initiation. Some data suggest that interventions delivered over several educational sessions can be helpful, but ongoing education is important.¹ Education for caregivers is also important. There may be no single best practice for counseling on clozapine, and the approach should be individualized. Starting with the benefits, as previously noted, can help frame why clozapine is being selected.

Education on risk should cover boxed warnings, including neutropenia, cardiac toxicities, seizures, and hypotension. Clozapine’s role as a third-line agent relates historically to how clozapine came to market and the risk of neutropenia.² However, based on current evidence, neutropenia is less common than previously cited, and after several years of clozapine use, the risk appears similar to some other antipsychotics. As such, there have been international consensus statements suggesting a reduction in the frequency of ANC monitoring after 18 weeks, and changes are forthcoming in Europe.³ Patients should have clear expectations about the monitoring plan. Helping patients overcome lab draw barriers can be important. Understanding the patient’s access to labs, transportation, as well as daily schedules, can help navigate these barriers. Finding local labs with more flexible hours, developing infrastructure for fingerstick ANC testing onsite, and exploring insurance coverage for medical transportation are examples.

Reviewing the risk of inflammatory reactions and self-monitoring is also important.⁴ Most notable is the risk of myocarditis or pericarditis, which can be monitored with laboratory test surveillance and through clinical assessment.⁵ Other inflammatory reactions may include interstitial nephritis, colitis, and hepatitis. Patients should report fever or chills, chest pain, shortness of breath, flu-like symptoms, or any other new physical symptoms. Slow titration is important for reducing the risk of inflammatory reactions, and patients should be aware their dose will be individualized.⁶ During clozapine treatment, acute inflammatory or infectious processes can cause a reduction in clozapine metabolism via an increase in circulating cytokines and their inhibition of CYP450, especially CYP1A2.⁷ It is important that patients report if they are feeling unwell and self-monitor for signs or symptoms of increasing clozapine levels, and it would be prudent to rule out neutropenia.

Patients should also be aware of the risk of severe hypotension if they miss more than 2 days of clozapine, and that returning to their prescribed dose can be problematic. During visits, I always ask about adherence and use this as a reminder to patients of the need to contact their care team or a health care professional for guidance if they miss several days of clozapine.

As mentioned, education should be ongoing during clozapine treatment. Using a systematic approach to monitoring [adverse] effects at each visit can support this. Repetition using a structured screening process can help patients learn what is important with clozapine monitoring. I find that patients, after several months, become aware of the questions I will be asking and what to look for between visits. Longitudinally, these points relate to dizziness, sedation, chest pain, shortness of breath, abdominal pain, constipation, sialorrhea, weight gain, increased urination, or nocturnal enuresis. From a practical standpoint, titrations can be complex, with changing doses and tablet strengths, or the use of multiple tablet strengths, which can cause confusion. These issues should be addressed by ensuring understanding and even providing a printed dosing calendar.

Smoking should also be assessed, along with education on the impact of smoking or smoking cessation on clozapine levels.⁸ Patients should report any changes to their smoking pattern or if they plan to quit. Smoking cessation can result in a 30% to 50% increase in clozapine levels. Notably, it is the polycyclic aromatic hydrocarbons within cigarette smoke that induce CYP1A2. Use of an electronic nicotine delivery system that heats liquids into vapor, chewing tobacco, or nicotine replacement therapy does not affect CYP1A2. However, switching back and forth between smoking and other noncombustible nicotine products can cause fluctuations in clozapine levels.

Pharmacy Times: As the author of the American Association of Psychiatric Pharmacists’ (AAPP) new Clozapine in Practice toolkit, what key resources or tools within it do you think will be most impactful for frontline pharmacists?

Leung: There are many great resources for clozapine-related information, and the AAPP Toolkit is just one. Key points of knowledge that I find under-recognized include dosing guidance based on genetic ancestry, detection and management of constipation, and the influence of inflammation on clozapine metabolism. The AAPP Clozapine Toolkit addresses these points. Pharmacists may also benefit from more detailed information from The Clozapine Handbook and The Maudsley Prescribing Guidelines in Psychiatry. These are also great resources. I’ve also included some additional citations that pharmacists may find useful. Finally, every setting and practice is different—the best resource may be one that is developed and vetted locally. Pharmacists may wish to develop their own “toolkits” in a multidisciplinary fashion to garner more widespread awareness of clozapine and support its use.

Key papers:

• de Leon J, Schoretsinitis G, Smith RL, et al. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry. 2022;55(2):73-86. doi:10.1055/a-1625-6388
• Siskind D, Northwood K, Pillinger T, et al. Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel. Lancet Psychiatry. 2026;13(1):77-86. doi:10.1016/S2215-0366(25)00098-7
• Wagner E, Korman N, Solmi M, et al; CAM Expert Group; Hasan A. Multidisciplinary consensus on prevention, screening and monitoring of clozapine-associated myocarditis and clozapine rechallenge after myocarditis. Br J Psychiatry. 2025;228(4):1-9. doi:10.1192/bjp.2025.89
• Carolan A, Hynes-Ryan C, Agarwal SM, et al. Metformin for the prevention of antipsychotic-induced weight gain: guideline development and consensus validation. Schizophr Bull. 2025;51(5):1193-1205. doi:10.1093/schbul/sbae205
• Correll CU, Agid O, Crespo-Facorro B, et al. A guideline and checklist for initiating and managing clozapine treatment in patients with treatment-resistant schizophrenia. CNS Drugs. 2022;36(7):659-679. doi:10.1007/s40263-022-00932-2
• Leung JG, Cotes RO. A call to action for starting clozapine: increasing clozapine use and safety in a post-REMS era. Focus (Am Psychiatr Publ). 2025;23(4):375-388. doi:10.1176/appi.focus.20250023

Pharmacy Times: Are there any emerging data, innovations, or policy changes on the horizon that you believe could further improve clozapine access or safety?

Leung: The biggest challenge right now with clozapine management relates to two European publications recommending reduced ANC testing. As mentioned, Europe will relax monitoring to weekly for 18 weeks, monthly until year 1 of clozapine treatment, and then quarterly from year 1 to 2. After 2 years, annual ANC monitoring has been proposed—not for neutropenia screening, but for the rare risk of hematologic malignancy associated with clozapine. However, currently the FDA still recommends monitoring ANC based on prescribing information: weekly for 6 months, every other week for months 6 to 12, then monthly indefinitely while prescribed clozapine.

This has left institutions navigating differences between FDA guidance and forthcoming European changes based on newer data. As it stands, clinicians may broach “off-label” monitoring with reduced frequency with patients. This decision, until FDA guidance changes, should be made through shared decision-making with patients and with review of the small risks of neutropenia after 18 weeks. Patients or caregivers should be able to monitor for signs and symptoms of infection, and documentation of these discussions would be important. Some guidance has been published by Meyer and Rubio.⁹

Innovations I look forward to include the development of and access to point-of-care CBC [complete blood cell count] and therapeutic drug monitoring devices. These may improve acceptability and access to testing. Currently, many institutions only have clozapine levels available as send-out tests, which may take days to weeks to return, limiting real-time use of results.

I hope that awareness of clozapine underuse and better understanding of its place in therapy will drive organizations to define metrics and quality measures that promote its use in the United States. In the UK, there are published quality metrics related to clozapine, but similar measures were considered in 2012 by the Department of Health and Human Services for Medicaid enrollees with schizophrenia. A clozapine-related measure was not added due to difficulties identifying treatment-resistant patients from claims data and concerns about small denominator size. ASHP’s Pharmacy Accountability Measures Work Group also decided not to add a clozapine measure given limited precedent.

Pharmacy Times: What advice would you give to pharmacists who are hesitant about getting more involved in clozapine management?

Leung: There is no better time to get more involved with clozapine management than today. Pharmacists can address these gaps through care initiatives, research, quality improvement, and education—helping to increase the use of clozapine and avoid potentially inappropriate antipsychotic polypharmacy. Data also suggest that delays in clozapine initiation may reduce response when it is eventually started.

Pharmacists advocate for evidence-based pharmacotherapy practices in all settings, and clozapine should be no exception. Many clinicians involved with clozapine have said something similar to, “We don’t avoid anticoagulation or chemotherapy simply because there is monitoring involved.” These agents, while carrying risks, are important treatments, and with appropriate monitoring, those risks can be mitigated.

Pharmacists can reflect on reasons why clozapine is avoided in order to provide the best care for patients. Addressing misconceptions and myths surrounding clozapine is a crucial step. It is not uncommon to hear, “A patient is not a good clozapine candidate due to a history of non-adherence.” While there are important considerations regarding laboratory adherence, patients still deserve a trial. In fact, some evidence suggests that clozapine may improve adherence secondary to its superior effectiveness compared with other agents.

REFERENCES

1. Verdoux H, Quiles C. Educational needs and psychoeducation interventions in clozapine users: a narrative review. Acta Psychiatr Scand. 2020;142(2):96-108. doi:10.1111/acps.13172

2. Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist Psychiatry. 2007;18(1):39-60. doi:10.1177/0957154X07070335

3. Mehta Z. EU to ease clozapine monitoring frequency after first year. Medscape. Accessed December 1, 2025. https://www.medscape.com/viewarticle/eu-ease-clozapine-monitoring-frequency-after-first-year-2025a1000ikn

4. Leung JG, Zhang L, Markota M, Ellingrod VL, Gerberi DJ, Bishop JR. A systematic review of clozapine-associated inflammation and related monitoring. Pharmacotherapy. 2023;43(12):1364-1396. doi:10.1002/phar.2887

5. Wagner E, Korman N, Solmi M, et al; CAM Expert Group, Hasan A. Multidisciplinary consensus on prevention, screening and monitoring of clozapine-associated myocarditis and clozapine rechallenge after myocarditis. Br J Psychiatry. 2025;228(4):1-9. doi:10.1192/bjp.2025.89

6. de Leon J, Schoretsanitis G, Smith RL, et al. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry. 2022;55(2):73-86. doi:10.1055/a-1625-6388

7. Clark SR, Warren NS, Kim G, et al. Elevated clozapine levels associated with infection: a systematic review. Schizophr Res. 2018;192:50-56. doi:10.1016/j.schres.2017.03.045

8. Leung JG, de Leon J, Frye MA, Singh B, Cotes RO, McElroy SL. The modernization of clozapine: a recapitulation of the past in the United States and the view forward. J Clin Psychopharmacol. 2022;42(6):565-580. doi:10.1097/JCP.0000000000001606

9. Meyer JM, Rubio JM. Clozapine monitoring in the post-REMS world: some guidance for clinicians. J Clin Psychiatry. 2025;86(2):25ac15898. doi:10.4088/JCP.25ac15898