Evaluating the adverse drug reactions to clozapine in populations of children and adolescents: insights from VigiBase data.

Abstract

Pharmacovigilance findings have marked clozapine use. Prescribers and package inserts worldwide focus on clozapine-induced neutropenia. The literature on clozapine adverse drug reactions (ADRs) for those under age 18 and their associated fatal outcomes is limited. Reports to the World Health Organization's global pharmacovigilance database (VigiBase) were analyzed among patients under 18 years of age extending from clozapine's introduction to June 1, 2022. There were 2825 reports of clozapine, including 42 fatal outcomes (relative lethality = 1.5% vs. 11.7% in all ages). After 280 cases were excluded (clozapine exposure during pregnancy, accidental exposure or unclear age), 2455 were included with ADRs during therapeutic use. Decreased white blood cell (WBC) count provided the most frequent aggregated ADR, accounting for 934 cases (37% of 2545), with only 1 fatal outcome (0.01%, 1/934). Suicide explained 7 of 27 (26%) non-duplicated fatal outcomes. Next in importance was clozapine-induced gastrointestinal hypomotility (CIGH) with 3 cases (11% of 27) and neuroleptic malignant syndrome with 2 cases (7% of 27). Agranulocytosis, aspiration, myocarditis, myocardiopathy and ventricular arrythmia led to single fatal cases. Based on these new findings and recent literature in all ages, to prevent fatal outcomes, child and adolescent psychiatrists need to shift their focus from severe neutropenia to other ADRs including pneumonia, respiratory aspiration and CIGH. In spite of its potential toxicity during overdoses, clozapine may have specific and strong anti-suicidal effects when compared with other antipsychotics. Child and adolescent psychiatrists need to take extreme precautions to avoid intentional overdoses when prescribing clozapine to patients with suicide risk.