Search

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.

Clozapine is an atypical antipsychotic indicated in patients with treatment-resistant schizophrenia which remains underused due to safety issues. Mechanisms behind these adverse effects are complex and not fully understood. They may involve immune-related mechanisms, direct toxic effects and oxidative stress. Clozapine-induced oxidative stress might indeed notably be involved in the onset of neutropenia, agranulocytosis, myocarditis, sialorrhea, and metabolic alterations. Therefore, the association of N-acetylcysteine (NAC), an easily accessible, low-cost and well tolerated antioxidant drug could be of interest in clozapine-treated patients to improve clozapine safety. Furthermore, according to recent studies NAC could help to improve schizophrenia symptoms. We believe that the use of NAC in the context of clozapine prescribing merits further study, as it could improve clozapine safety which may lead to a wider use and ultimately improve the healthcare of thousands of patients. NAC could also secondarily show positive knock-on effects for the patients by improving clinical symptoms of schizophrenia in synergy with clozapine, and by reducing substance abuse and thus by improving the patient's overall condition. However, given the rarity of clozapine-induced severe adverse effects, only a large volume of data (e.g., National adverse events monitoring) could assess the benefits of NAC on clozapine safety., (© 2020 John Wiley & Sons Ltd.)

Introduction: Clozapine is primarily reserved for treatment-resistant schizophrenia due to safety concerns associated with its use. Infections have been reported with clozapine, which may lead to elevated serum levels of the drug. However, the existing literature on this topic is limited. Therefore, we conducted a study using VigiBase® to investigate the potential over-reporting of infections associated with clozapine, to explore the presence of dosedependency, and to investigate the underlying mechanism. Methods: Disproportionality analyses were performed using VigiBase to assess the association between clozapine and all types of infections, the association between clozapine-associated infections and neutropenia, the association between clozapine-associated infections and agranulocytosis, the dose–effect relationship between clozapine and infections, and the interaction between clozapine and the main strong CYP450 inhibitors using reports carried out until 11 April 2023. Results: A statistically significant signal of infections was observed with clozapine, as indicated by an information component of 0.43 [95% CI: (0.41–0.45)]. The most commonly reported infections were respiratory and gastrointestinal in nature. Neutropenia showed weaker association with clozapine-associated reports of infections compared to other clozapine-associated reports [X2 (1, N = 204,073) = 454; p < 0.005], while agranulocytosis demonstrated a stronger association with clozapine-associated reports of infections [X2 (1, N = 204,073) = 56; p < 0.005]. No evidence of dose-dependency was observed. Among the 17 tested CYP inhibitors, significant drug–drug interactions were found with clarithromycin, metronidazole, valproic acid, lansoprazole, omeprazole, amiodarone, and esomeprazole. Discussion: Our study revealed a significant safety signal between clozapine use and infections, predominantly respiratory and gastrointestinal infections. The coadministration of clozapine with valproic acid or proton pump inhibitors may potentially contribute to an increased risk of infection. Further vigilance is warranted in clinical practice, and consideration of therapeutic drug monitoring of clozapine in cases involving concomitant use of these drugs or in the presence of infections may be beneficial. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]