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. 2025 May-Jun;45(3):197-218.
doi: 10.1097/JCP.0000000000001990. Epub 2025 Apr 9.

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

Jose de Leon, Ross J Baldessarini, Richard Balon  1 , John Bilbily  2 , Stanley N Caroff, Leslie Citrome  3 , Christoph U Correll, Robert O Cotes  4 , John M Davis  5 , Lynn E DeLisi  6 , Justin Faden  7 , Oliver Freudenreich  8 , David R Goldsmith  4 , Ronald Gurrera, Richard C Josiassen  9 , John M Kane, Deanna L Kelly  10 , Matcheri S Keshavan  11 , Robert S Laitman  12 , Y W Francis Lam  13 , Jonathan G Leung  14 , Raymond C Love  15 , Betsy McCollum  16 , Ian R McGrane  17 , Jonathan M Meyer  18 , Henry A Nasrallah  19 , Frederick C Nucifora Jr  20 , Anthony J Rothschild  21 , Jose M Rubio, Martha Sajatovic  22 , Deepak K Sarpal  23 , Georgios Schoretsanitis, Mujeeb Shad  24 , Charles Shelton, Leo Sher  25 , Balwinder Singh  26 , Sandarsh Surya  27 , Theodore R Zarzar  28 , Emilio J Sanz, Carlos De Las Cuevas  29
Affiliations

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

Jose de Leon et al. J Clin Psychopharmacol. 2025 May-Jun.

Abstract

Purpose/background: This 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).

Methods: US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023.

Findings/results: The 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/conclusions: To 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.

Keywords: clozapine/adverse effects; clozapine/therapeutic use; clozapine/toxicity; drug labeling; schizophrenia.

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Figures

FIGURE 1
FIGURE 1
Clozapine-associated fatal outcomes including a broad definition of severe neutropenia. There were 64 fatal outcomes associated with agranulocytosis, 100 with neutropenia, 49 with leukopenia and 36 with granulocytopenia. The sum of these reports with fatal outcomes is 249 (64 + 100 + 49 + 36 = 249). There were only 218 individual fatal outcomes; this means that 31 (249–218 = 31) reports were eliminated as some fatal outcomes had more than 1 label.
FIGURE 2
FIGURE 2
Clozapine-associated fatal outcomes including a broad definition of pneumonia. There were 558 fatal outcomes associated with “pneumonia” and 115 with “aspiration pneumonia.” The sum of these reports with fatal outcomes is 796 (558 + 115 = 796). There were only 674 individual fatal outcomes; this means that 122 (796–674 = 122) reports were eliminated as some fatal outcomes had more than 1 label.
See this image and copyright information in PMC

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