Fatal Outcomes in Use of Clozapine: A VigiBase Study of 6402 Women and 11,222 Men

In 1975, US clozapine studies stopped after pharmacovigilance identified 8 Finnish fatal outcomes during agranulocytosis. In 1989, clozapine was approved with hematological monitoring for treatment-resistant schizophrenia. This study focuses on over/underrepresented fatal outcomes in female versus male adults on clozapine.

Worldwide fatal outcomes in VigiBase were included from inception to January 15, 2023. There were 6402 female adult cases and 11,222 adult male controls who were stratified by age (young, 18 to 44 years; middle-aged, 45 to 64 years; and geriatric ≥65 years). In these 6 subgroups, fatal outcomes of clozapine ADRs were ranked by frequency; over/underrepresentation was determined by comparison with corresponding male controls using univariate odds ratios (ORs), their 95% CIs and adjusted ORs (aORs) after adjusting for major confounders.

The unspecific label "death" accounted for around 40% of fatal outcomes. Pneumonia was the most frequent specific fatal outcome in both sexes in the middle-aged and geriatric groups. In the young group, pulmonary embolism was the most frequent specific fatal outcome in females at 8.0% (92/1147) versus 3.9% (126/3233) in males. Pulmonary embolism was overrepresented in young (adjusted OR = 2.25; 95% CI, 1.70-2.98) and in middle-aged females (aOR = 1.46, CI, 1.07-2.00). Myocardial infarction was underrepresented in young (aOR = 0.61; CI, 0.43-0.87) and in middle-aged females (aOR = 0.52; CI, 0.29-0.78).

Young females on clozapine are at lower risk of dying from agranulocytosis, 1.7% (19/1147) than from pulmonary embolism, 8.0% (92/1147). Thus, focusing on pulmonary embolism is key to saving lives in this group. Future studies need to replicate these findings.