Introduction: In response to the COVID-19 pandemic, the FDA announced enforcement discretion of the clozapine Risk Evaluation and Mitigation Strategy (REMS) program on March 22, 2024. The impact of these changes on rates of Clozapine related adverse-events and reporting pattern has not been examined to-date. Using the FDA Adverse Event Reporting System (FAERS) database, we examined the effect of this regulatory change on the reporting patterns of Clozapine-related adverse events. Methods: Data from the FAERS database from January 2018 to June 2024 was obtained. Interrupted time-series models were employed to evaluate the total number of reported adverse events and event-specific rates for death, agranulocytosis, neutropenia, and myocarditis, with March 22, 2020, as the index date for FDA enforcement discretion. Results: FAERS database reports were predominantly from USA (41.63%), with majority of reports submitted by physicians (37.88%) and pharmacists (37.83%). Total reported counts per month and death count per month did not show significant changes in trend. The reported death proportion and myocarditis count showed a significant downward trend (p = 0.002 and p = 0.005, respectively). No significant trend changes were seen in reporting of agranulocytosis and neutropenia (count per month and proportion). Discussion: The FDA's enforcement discretion of clozapine REMS program during the COVID-19 pandemic was associated with a significant reduction in reporting of clozapine-induced myocarditis and death, but not of agranulocytosis or neutropenia. Whether these changes reflect true change in rates, preferential attribution of these adverse-events to COVID-19 or change in reporting patterns warrant further verification.

The authors have declared no competing interest.

No Funding received

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data is obtained from the publicly available FAER's dataset.