ArticleJournal of clinical psychopharmacology
Letter to the FDA Proposing Major Changes in the US Clozapine Package Insert Supported by Clozapine Experts Worldwide. Part II: A Review of Fatal Outcomes in US Pharmacovigilance Data and Proposed Changes.
Article in Journal of clinical psychopharmacology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Ethics as if Your Life Depended on It.Journal of empirical research on human research ethics : JERHRE · 2026Article
- VigiBase suggests that the number of deaths by suicide in adolescents with schizophrenia as a result of not taking clozapine may be much higher than the number of deaths from agranulocytosis after taking clozapine.European child & adolescent psychiatry · 2026Article
- Optimizing Clozapine Monitoring in Older Adults: A Proposal for Ethnicity- and Sex-Informed Monitoring in Japanese Geriatric Patients.Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society · 2026Article
- Relaxation of Japan's clozapine monitoring system is urgently needed: Adding 10,000 future prescriptions may prevent up to 400 schizophrenia-related suicides and cost 1 death by agranulocytosis.PCN reports : psychiatry and clinical neurosciences · 2026Article
- Management of Parkinson's disease psychosis-a European perspective.The Lancet regional health. Europe · 2026Review
- Review
- Efficacy and Safety of Twelve Anti-Dyskinetic Drugs in Parkinson's Disease: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.European journal of neurology · 2025Review
- Clozapine and Regulatory Inertia: Revisiting Evidence, Risks, and Reform.Healthcare (Basel, Switzerland) · 2025Article
- Elevated neutrophil-to-lymphocyte ratios correlate with increased clozapine concentration-to-dose ratios during titration.Schizophrenia (Heidelberg, Germany) · 2025Article
- Letter to the FDA Proposing Major Changes in the US Clozapine Package Insert Supported by Clozapine Experts Worldwide. Part I: A Review of the Pharmacokinetic Literature and Proposed Changes.Journal of clinical psychopharmacologyReview
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Authors and funding
40 authors.
Funding
Abstract
PURPOSE/
backgroundThis is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia).
methodsUS reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. FINDINGS/
resultsThe US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. IMPLICATIONS/
conclusionsTo help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.
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