Neurocognitive impairment in females with breast cancer treated with endocrine therapy and CDK4/6 inhibitors: a pharmacovigilance study using the World Health Organization's database.

Importance: Endocrine therapies (ETs) and inhibitors of cyclin-dependent kinases-4/6 (iCDK4/6s) are a standard treatment in breast cancer. However, data on potential neurocognitive impacts remain inconsistent for ET and are scarce for iCDK4/6s. Objective: To evaluate whether ET and iCDK4/6s are associated with neurocognitive impairment (NCI). Methods: We used observational, real-world cases of NCI from the World Health Organization's database VigiBase® to perform disproportionality analysis. Cases were defined as any symptom of NCI in females treated with ETs or iCDK4/6s. The study period was from the date of the first adverse event reported in VigiBase® with iCDK4/6s (1 January 2014) until the date of data extraction (16 March 2022). In our primary analysis, we calculated the reporting odds ratio (ROR) adjusted for age to identify a potential association between NCI and individual ETs in isolation or in combination with iCDK4/6s. We also performed subgroup analyses by the NCI class. Results: We identified 2.582 and 1.943 reports of NCI associated with ETs and iCDK4/6s, respectively. NCI was significantly associated with each ET [anastrozole: n = 405, aROR = 1.52 (95% CI: 1.37-1.67); letrozole: n = 741, aROR = 1.37 (95% CI: 1.27-1.47); exemestane: n = 316, aROR = 1.37 (95% CI: 1.22-1.53); tamoxifen: n = 311, aROR = 1.25 (95% CI: 1.12-1.40); and fulvestrant: n = 319, aROR = 1.19 (95% CI: 1.06-1.33)] and only with palbociclib for iCDK4/6s [n = 1,542, aROR = 1.41 (95% CI: 1.34-1.48)]. Conclusion: These findings suggest that in females treated for breast cancer, all ETs may be associated with NCI. However, amongst iCDK4/6s, NCI may be specific to palbociclib. NCI most frequently involved learning and memory as well as language. Neurocognitive impact of treatments requires better consideration and management.

Infections associated with clozapine: a pharmacovigilance study using VigiBase®.

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 dose-dependency, 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 co-administration 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.

Hypoxia Associated With Dihydropyridine Calcium Channel Inhibitors: A Pharmacovigilance Study in VigiBase.

Due to their negative effects on hypoxic pulmonary vasoconstriction, dihydropyridine calcium channel inhibitors (DCCIs) can lead to hypoxia in patients with a pulmonary shunt. To date, only preclinical studies and case reports have focused on this potential adverse drug reaction. We aimed to assess the reporting association between DCCIs and hypoxia using the World Health Organization pharmacovigilance database (VigiBase). We performed a disproportionality analysis to evaluate the strength of the reporting association between i.v. clevidipine and nicardipine, thought to be a surrogate of patients in the intensive care unit, and hypoxia. The information component and the lower end of its 95% credibility interval were used to evaluate disproportionality. A description of the cases was made. Secondary outcomes included the association between all DCCIs and hypoxia compared with other treatments with similar indications, urapidil and labetalol, regardless of the route of administration. Association between oral nicardipine and hypoxia was also searched. A statistically significant signal of hypoxia was found for intravenous clevidipine and nicardipine. The time to onset was reported with a median of 2 days (interquartile range 1.5-4.5). Four dechallenges were performed with intravenous nicardipine, leading to the resolution of the symptoms. Regardless of the route of administration, a signal of hypoxia was also found for nimodipine but not for other drugs, including comparators. For nicardipine no signal of hypoxia was found with the oral route of administration. Our pharmacovigilance database analysis showed a significant association between the use of intravenous DCCIs and hypoxia.

Rhabdomyolysis with Co-Administration of Statins and Antiplatelet Therapies-Analysis of the WHO Pharmacovigilance Database.

PURPOSE: While statins and antiplatelet therapies are largely prescribed together worldwide, limited information is available on the safety of their association regarding rhabdomyolysis occurrence. We aimed to assess the reporting of rhabdomyolysis in patients treated with a combination of statin and antiplatelet therapy, compared to statin alone. METHODS: We used the World Health Organization pharmacovigilance database (VigiBase®) to compare the rhabdomyolysis reporting between statin (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) plus antiplatelet therapy (acetylsalicylic acid, clopidogrel, prasugrel and ticagrelor) groups versus statin alone groups, for each statin and antiplatelet therapy. Study setting was restricted to patients aged 45 or older, including reports up until 1st September, 2021. We computed reporting Odds-Ratio (ROR) and their 95% confidence interval (CI) to quantify the disproportionality between groups, adjusted on age and sex. RESULTS: Among the 11,431,708 reports of adverse reactions, we extracted 9,489 cases of rhabdomyolysis in patients treated with statins, of whom 2,464 (26%) were also treated with antiplatelet therapy. The reporting of rhabdomyolysis was increased when ticagrelor was associated with atorvastatin (ROR 1.30 [1.02-1.65]) or rosuvastatin (ROR 1.90 [1.42-2.54]) compared to the respective statin alone but did not change when aspirin, clopidogrel or prasugrel were considered. CONCLUSION: Rhabdomyolysis reporting was increased when ticagrelor -but not other antiplatelet agents- was notified with the most prescribed statins in practice. This finding needs to be considered by physicians especially in high-risk patients.

Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase.

AIMS: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). METHODS: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. RESULTS: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. CONCLUSION: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.

COVID-19 vaccines associated with vasovagal malaise: A retrospective study in two mass vaccination centers and analysis of the WHO pharmacovigilance database.

The association between COVID-19 vaccines and vasovagal malaise (VVM) has recently been reported in the literature. Our study aimed to describe COVID-19 vaccines associated VVM cases and to identify risk factors of COVID-19 vaccines associated VVM. To this end, we performed a descriptive study of VVM reports associated with COVID-19 vaccines from two French mass COVID-19 vaccination centers. We also extracted reports of VVM associated with all-COVID-19 vaccines in VigiBase®, the World Health Organization (WHO) pharmacovigilance database to analyze demographic data. In the two French mass vaccination center database, 408 entries reported VVM after the standard administration of tozinameran - Pfizer® (1.63/1,000 vaccinated persons). Of these cases, 213 (52.2%) occurred in women, and 193 (47.3%) occurred in the 18-29 year-old (yo) age group. In 232 cases (56.8%), patients had a history of anxiety related to needles or medical visits, 213 (52.2%) reported a fear of COVID-19 vaccination in particular, and 233 (57.1%) had a history of VVM. In VigiBase®, 336,291 notifications of COVID-19 vaccines associated with VVM were identified in the adult population during the period of analysis. The most reported age class was 18-44 years (52.4%), and women represented 71.7% of the reports. Reporting widely differed depending on the country. This study, performed in real-life conditions, highlights that VVM is associated with all-COVID-19 vaccines. Young age and history of anxiety related in young adults could be a triggering factor of vaccines-associated VVM. Further studies are needed to confirm our results.

Transverse Myelitis Following SARS-CoV-2 Vaccination: A Pharmacoepidemiological Study in the World Health Organization's Database.

BACKGROUND: Transverse myelitis (TM) has recently been associated by health authorities with Ad26.COV2.S (Janssen/Johnson & Johnson), one of the 5 US Food and Drug Administration (FDA) or European Medicines Agency (EMA) labeled severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. It is unknown whether a similar association exists for the other FDA or EMA labeled SARS-CoV-2 vaccines (BNT162b2 [Pfizer/BioNTech], mRNA-1273 [Moderna], ChAdOx1nCov-19 [Oxford-AstraZeneca], and NVX-CoV2373 [Novavax]). This study aimed to evaluate the association between SARS-CoV-2 vaccine class and TM. METHODS: This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from VigiBase, the World Health Organization's pharmacovigilance database. We first conducted a disproportionality analysis with the information component (IC) using the reports of TM that occurred within 28 days following exposure to the FDA or EMA labeled SARS-CoV-2 vaccines, from December 1, 2020 (first adverse event related to a SARS-CoV-2 vaccine) to March 27, 2022. Second, we analyzed the clinical features of SARS-CoV-2 vaccine-associated TM cases reported in VigiBase. RESULTS: TM was significantly associated both with the messenger ribonucleic acid (mRNA)-based (n = 364; IC025  = 0.62) and vector-based (n = 136; IC025  = 0.52) SARS-CoV-2 vaccines that are authorized by the FDA or the EMA. CONCLUSIONS: Findings from this observational, cross-sectional pharmacovigilance study showed that mRNA-based and vector-based FDA/EMA labeled SARS-CoV-2 vaccines can be associated with TM. However, because TM remains a rare event, with a previously reported rate of 0.28 cases per 1 million vaccine doses, the risk-benefit ratio in favor of vaccination against SARS-CoV-2 virus remains unchallenged. Rather, this study suggests that clinicians should consider the diagnosis of TM in patients presenting with early signs of spinal cord dysfunction after SARS-CoV-2 vaccination. ANN NEUROL 2022;92:1080-1089.

Neonatal Hypotonia Following in Utero Exposure to Antidepressant Drugs.

Associations between fetal exposure to antidepressants and neonatal hypotonia were studied using VigiBase and the French PharmacoVigilance Database. We identified significant associations between neonatal hypotonia and clomipramine, venlafaxine, and imipramine. Reports from the French database implicated prolonged fetal exposure. Neonatal hypotonia may be associated with in utero exposure to antidepressants.

A Worldwide Pharmacoepidemiologic Update on Drug-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in the Era of Targeted Therapies.

OBJECTIVE: The literature supporting the role of a specific drug in the onset of drug-induced antineutrophil cytoplasmic antibody-associated vasculitis (AAV) mainly relies on case reports or short series and implicates old treatments. The advent of new treatments may have modified the epidemiology of these adverse drug reactions. This study was undertaken to update the list of drugs associated with AAV by using a pharmacovigilance-based data mining approach. METHODS: We collected data on adverse drug reactions reported using the Medical Dictionary for Regulatory Activities preferred term "anti-neutrophil cytoplasmic antibody positive vasculitis" up to November 2020 from the World Health Organization pharmacovigilance database (VigiBase). For each retrieved drug, a case-noncase analysis was performed, and disproportionate reporting was calculated by using the information component (IC). A positive IC025 value, which is the lower end of the 95% credibility interval, was considered significant. RESULTS: A total of 483 deduplicated individual case safety reports of drug-induced AAV involving 15 drugs with an IC025 >0 were retrieved. Of the individuals with drug-induced AAV for whom data on sex were available (n = 371), 264 (71.2%) were women. The median age at onset of drug-induced AAV was 62 years (quartile 1 [Q1]-Q3 45-72 years), and the median time from the introduction of the suspected drug to the onset of drug-induced AAV was 9 months (Q1-Q3 1-36 months). Drug-induced AAV was considered serious in 472 (98.1%), and was fatal in 43 (8.9%), of 481 cases. The drugs associated with the highest disproportionate reporting were hydralazine, propylthiouracil, thiamazole, sofosbuvir, minocycline, carbimazole, mirabegron, and nintedanib. CONCLUSION: Our findings strengthen the evidence of an association of AAV with previously suspected drugs, but also identify 3 new drugs that may cause drug-induced AAV. Particular attention should be given to these drugs by prescribers and in experimental studies.

General medicine and notification of adverse reactions: contributions of health insurance representatives / Cabinets de médecine générale et notification des effets indésirables médicamenteux : expertise d'un délégué de l'Assurance maladie

INTRODUCTION: In order to reduce the under-reporting of adverse drug reactions (ADR) in general practice, the Caen Normandie regional pharmacovigilance center (CRPV) has implemented a training program for the French health insurance representatives (DAM) of the Manche department in order to raise awareness among general practitioners (GPs) to ADR reporting. PURPOSE OF RESEARCH: During quarterly visits of DAM to GPs, the mode of operation and the value of pharmacovigilance reporting was presented. This pilot study presents the impact of these DAM visits to GPs in term of ADRs reporting quantification. RESULTS: Assessment of this first year showed a doubling of ADR reporting by GPs of the Manche department in 2019 compared to 2017 and 2018. This phenomenon was not found in the two control departments (departments of Calvados and Orne) where the information had not been issued. These ADRs first concerned drugs of the renin-angiotensin system, then psychotropic drugs and anti-infectives. These were cutaneous, then neurological and gastrointestinal ADRs, preferentially affecting women. CONCLUSIONS: This experimentation should continue on a larger scale. The longer-term evaluation of this tool also requires evaluating its relevance.

Introduction: Pour réduire la sous-notification des effets indésirables médicamenteux (EIM) en médecine générale, le centre régional de pharmacovigilance (CRPV) Caen Normandie a mis en place une formation pour les délégués de la Caisse primaire d'assurance maladie de la Manche (CPAM 50) afin de sensibiliser les médecins généralistes (MG) à la déclaration des EIM. Ainsi, lors de la visite trimestrielle des délégués de la CPAM 50 aux MG, il était présenté le mode de fonctionnement et l'intérêt des déclarations de pharmacovigilance. But de l'étude: Cette étude pilote présente l'influence de ces visites post-formation des délégués de la CPAM 50 sur le nombre d'EIM déclarés. Résultats: Le bilan de cette première année de visites montre le doublement des EIM déclarés par les MG du département de la Manche en 2019 par rapport aux années 2017 et 2018. Ce phénomène n'a pas été retrouvé dans les deux départements témoins (départements du Calvados et de l'Orne), où l'information n'avait pas été délivrée. Ces EIM concernaient d'abord les médicaments du système rénine-angiotensine, puis les psychotropes et les anti-infectieux. Il s'agissait d'EIM cutanés puis neurologiques et gastro-intestinaux touchant préférentiellement les femmes. Conclusions: Cette expérimentation devra se poursuivre à plus large échelle. L'évaluation à plus long terme de ce dispositif permettra aussi d'en évaluer la pertinence.

Association Between Disease-Modifying Therapies Prescribed to Persons with Multiple Sclerosis and Cancer: a WHO Pharmacovigilance Database Analysis.

The risk of cancer associated with persons with multiple sclerosis (pwMS) prescribed with disease modifying therapies (DMTs) is not well established. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database: VigiBase®. All consecutive reports of DMTs prescribed to pwMS (alemtuzumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-ß, natalizumab, ocrelizumab, and teriflunomide), and their serious adverse event cases were eligible, excluding those reporting immunosuppressant DMTs used as anticancer therapies. The primary outcome was the multivariate odds ratio of cancer reporting (r-OR) for DMTs prescribed to pwMS after imputation of missing data. There were 5966 cancer cases from 240,993 reports of DMTs prescribed to pwMS. After adjustments on age, sex, and geographical region, natalizumab (r-OR 1.74, 95% CI 1.63-1.87), interferon-ß (r-OR 1.39, 95% CI 1.30-1.49), dimethyl fumarate (r-OR 1.35, 95% CI 1.25-1.46), and fingolimod (r-OR 1.15, 95% CI 1.06-1.24) were significantly associated with a greater cancer reporting, whereas alemtuzumab, glatiramer acetate, ocrelizumab, and teriflunomide were not, in the disproportionality analysis. As exploratory analyses, upper aerodigestive tract, breast, urinary including the male genitourinary tract, and nervous system cancers were associated with natalizumab, interferon-ß, and dimethyl fumarate. Fingolimod was only associated with skin cancer types. Cancer cases reporting these four DMTs prescribed to pwMS were younger in age than for non-pwMS drugs in the VigiBase® (p < 0.0001). A close and regular cancer screening in pwMS treated with natalizumab, interferon-ß, dimethyl fumarate, and fingolimod may be warranted, even for persons at a younger age. Trial Registration NCT04237337.

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

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.

Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukaemia, for which data are scarce. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukaemia cases reported in WHO's pharmacovigilance database (VigiBase). METHODS: We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age ≥18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov. If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov, publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov, NCT04326023. FINDINGS: For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13-6·14], p=0·026) with no between-study heterogeneity (I2=0%, χ2 p=0·91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0·73% (95% CI 0·50-1·07; I2=0%, χ2 p=0·87; 21 events out of 4533 patients) and across placebo groups was 0·47% (0·26-0·85; I2=0%, χ2 p=1·00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9·8 months (IQR 3·6-17·4; n=96) and median latency period since first exposure to a PARP inhibitor was 17·8 months (8·4-29·2; n=58). Of 104 cases that reported outcomes, 47 (45%) resulted in death. INTERPRETATION: PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting. FUNDING: None.

Could N-acetylcysteine improve the safety of clozapine?

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.