Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project.

Importance: The rapid spread and mortality associated with COVID-19 emphasized a need for surveillance system development to identify adverse events (AEs) to emerging therapeutics. Bradycardia is a remdesivir infusion-associated AE listed in the US Food and Drug Administration-approved prescribing information. Objective: To evaluate the magnitude and duration of bradycardic events following remdesivir administration. Design, Setting, and Participants: A multicenter cohort study of patients with recorded heart rate less than 60 beats per minute within 24 hours after administration of a remdesivir dose was conducted between November 23, 2020, and October 31, 2021. Participants included patients hospitalized with COVID-19 at 15 medical centers across the US. Patients excluded had AEs unrelated to bradycardia, AEs in addition to bradycardia, or first onset of bradycardia after 5 remdesivir doses. Exposures: Remdesivir administration. Main Outcomes and Measures: Linear mixed-effect models for the minimum HR before starting remdesivir and within 24 hours of each dose included doses as fixed effects. Baseline covariates were age (≥65 years vs <65 years), sex (male vs female), cardiovascular disease history (yes vs no), and concomitant use of bradycardia-associated medications. The interactions between variables and doses were considered fixed-effects covariates to adjust models. Results: A total of 188 patients were included in the primary analysis and 181 in the secondary analysis. The cohort included 108 men (57.4%); 75 individuals (39.9%) were non-Hispanic White and mean (SD) age was 61.3 (15.4) years. Minimum HR after doses 1 to 5 was lower than before remdesivir. Mean minimum HR was lowest after dose 4, decreasing by -15.2 beats per minute (95% CI, -17.4 to -13.1; P < .001) compared with before remdesivir administration. Mean (SD) minimum HR was 55.6 (10.2) beats per minute across all 5 doses. Of 181 patients included in time-to-event analysis, 91 had their first episode of bradycardia within 23.4 hours (95% CI, 20.1-31.5 hours) and 91 had their lowest HR within 60.7 hours (95% CI, 54.0-68.3 hours). Median time to first bradycardia after starting remdesivir was shorter for patients aged 65 years or older vs those younger than 65 years (18.7 hours; 95% CI, 16.8-23.7 hours vs 31.5 hours; 95% CI, 22.7-39.3 hours; P = .04). Median time to lowest HR was shorter for men vs women (54.2 hours; 95% CI, 47.3-62.0 hours vs 71.0 hours; 95% CI, 59.5-79.6 hours; P = .02). Conclusions and Relevance: In this cohort study, bradycardia occurred during remdesivir infusion and persisted. Given the widespread use of remdesivir, practitioners should be aware of this safety signal.

Ivermectin associated adverse events in the treatment and prevention of COVID-19 reported to the FACT pharmacovigilance project.

BACKGROUND: In August 2021, the Centers for Disease Control and Prevention (CDC) released a health alert following the rapid increase in ivermectin prescriptions and reports of severe illness associated with use of products containing ivermectin for the prevention or treatment of COVID-19 infections. The United States Food and Drug Administration (FDA) and the CDC have explicitly discouraged the use of ivermectin in the prevention or treatment of COVID-19 outside of clinical trials. The study aims to describe the adverse events (AEs) related to ivermectin use for the prevention or treatment of COVID-19. METHODS: This is a prospective case series of adverse events related to therapeutics used in the prevention or treatment of COVID-19 submitted to the FDA ACMT COVID-19 ToxIC (FACT) Pharmacovigilance Project sub-registry between October 2020 and December 2021. This is an ongoing toxico-surveillance system at 15 major academic medical centers in 12 states. Data collected included sociodemographics, exposure related information including dose, frequency, route, duration, and reason for taking ivermectin as well as a clinical description of the adverse event and the outcome. RESULTS: A total of 40 patients who developed AEs following ivermectin use were reported to FACT over 15 months. Self-medication with veterinary formulations were reported in 18/40 patients Thirty-three patients presented to emergency departments and nineteen patients were admitted to the hospital. Patients reported using ivermectin for prevention (24/40), treatment of symptoms (19/40), and for treatment of documented COVID-19 (8/40). Neurological toxicity was the most frequent finding. Fifteen patients had minor symptoms while 25 developed severe toxicity. CONCLUSIONS: Ivermectin use for the attempted treatment of COVID-19 has potential adverse health effects primarily related to neurological function. This is especially true when patients are self-treating with this medication and when they are using formulations intended for non-human use.