Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase^®

Abstract

Background Clozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database. Methods We performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report. Results Of the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75–10.77) and leukaemia (aROR 3.54, 95% CI 2.97–4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2–9.9) for malignant lymphoma and 2.5 years (IQR 0.6–7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association. Conclusions Clozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.

Rapid review of suspected adverse drug events due to remdesivir in the WHO database; findings and implications

“…This principally involved interrogating the VigiBase®, which is the global pharmacovigilance database maintained by the WHO, and previously used to evaluate ADEs associated with hydroxychloroquine [24,25]. VigiBase® contains all ICSRs of adverse events collected by the national pharmacovigilance centers from over 130 countries [26][27][28]. An ICSR is an anonymised report for a single individual (patient) who was given suspected drug, who experienced single or multiple ADEs.…”

Could N‐acetylcysteine improve the safety of clozapine?

“…Clozapine has been widely available for decades but remains underused due to safety issues, which include severe hematologic and cardiovascular adverse effects. Hematologic adverse effects include neutropenia, agranulocytosis (incidence of 3.0% and 1.0% over a follow-up of 4.5 years in the United Kingdom and Ireland, respectively), and more rarely anemia, thrombocytopenia but also potentially hematologic malignancies (Chrétien et al, 2020). Cardiovascular adverse effects include myocarditis (incidence of 3.16% over a follow-up of 6.5 years; Higgins, San, Lagnado, Chua, & Mihic, 2019).…”

“…Clozapine is bioactivated in a nitrenium ion by cytochromes P450 and myeloperoxidase system in leukocytes and their precursors. This nitrenium ion is a reactive species which has been associated with the formation of DNA adducts and cells apoptosis and is the probable cause of hematologic adverse effects (Chrétien et al, 2020). It has been shown in vitro that this clozapine nitrenium ion is normally detoxified by conjugating to glutathione (Dragovic, Boerma, van Bergen, Vermeulen, & Commandeur, 2010).…”

Response to ‘The association of clozapine and haematological malignancies needs to be replicated by other studies and more importantly by analyses of subsamples from VigiBase’

“…We have read with interest the reply by De Leon et al (Leon, las Cuevas, Sanz, & Verdoux, 2020 a ) about our work assessing the association between clozapine and haematological malignancies (Chrétien et al, 2020) in VigiBase ® . We are grateful that De Leon et al showed such interest in our study and we think that their remarks merit further explanations to be fully addressed.…”