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Fatal and life-threatening ADRs associated with paliperidone palmitate: an observational study in the French pharmacovigilance database

Abstract Introduction Paliperidone palmitate (PP), a long‐acting intramuscular formulation of paliperidone, has been marketed in Europe within the last 10 years and provides an important treatment option for patients with schizophrenia. Our aim was to describe PP-related adverse drug reactions (ADRs) leading to death or life-threatening events, specifying their main clinical and pharmacological characteristics. Methods This observational study was a retrospective review of PP-related ADRs in the French pharmacovigilance database between January 1, 2013, and December 31, 2019. Results Out of 473 PP-related ADRs, we identified 13 deaths and 14 life-threatening events. ADRs were primarily cardiorespiratory (n = 17; 63%). Other symptoms observed were mainly metabolic (n = 4), digestive (n = 4), and neurological (n = 4). Cardiorespiratory symptoms were generally observed within first 6 months after initiation of treatment (11 out of 17 cases), unlike metabolic disorders (all 4 cases 12–21 months after initiation). Cardiac arrests and sudden unexpected deaths occurred 10–14 days after the last PP once-monthly injection (23 cases) or 11–24 days after the last PP three-monthly injection (remaining 4 cases). No PP blood concentration assays were performed for these patients. Discussion In this study, PP-related ADRs leading to death or life-threatening events mainly presented with cardiorespiratory symptoms and tended to occur in the first 6 months after the initiation of treatment and within postadministration periods aligned with peak plasma PP concentrations. The hypothesis of supratherapeutic drug concentrations following intramuscular PP injection must be raised. Conclusion PP-related ADRs leading to death or life-threatening events mainly presented with cardiorespiratory symptoms. Cardiac arrests and sudden unexpected deaths following initiation of PP treatment could be due to supratherapeutic drug concentrations. This study highlights the need to monitor blood concentrations of PP. Key points Adverse reactions to paliperidone palmitate can lead to death or life-threatening events. It is hypothesized that cardiac arrests and sudden unexpected deaths following initiation of paliperidone palmitate treatment could be due to supratherapeutic drug concentrations. This paper proposes the need to monitor blood concentrations of paliperidone palmitate in future studies.