How did off‑label and veterinary use of ivermectin during the COVID‑19 pandemic affect reported adverse events and pharmacovigilance signals?
Executive summary
Off‑label and veterinary use of ivermectin during the COVID‑19 pandemic produced a measurable uptick in reported adverse events and produced clearer pharmacovigilance “signals,” driven largely by misuse, overdosing and ingestion of veterinary formulations rather than routine, licensed dosing; however, clinical-trial data and systematic reviews show mixed findings about overall event rates, complicating causal interpretation [1] [2] [3]. The net effect was to strain poison‑control and pharmacovigilance systems, generate high‑visibility case series of severe toxicity, and increase regulatory and professional warnings even as randomized trials did not demonstrate clinical benefit [4] [5] [6].
1. The observable signal: more reports, more severity recorded
Global pharmacovigilance databases registered a sharp rise in spontaneous reports of ivermectin adverse drug reactions after it was touted for COVID‑19; VigiBase and other surveillance systems documented a large percentage increase in notifications and a non‑trivial number of severe outcomes including deaths and hospitalizations (between 2019–2022 VigiBase data showed thousands of reports with 5.7% classified as severe, and 1.6% as deaths or life‑threatening conditions) [1] [7].
2. How off‑label and veterinary misuse drove case reports
Case series and poison‑center surveillance linked many of the new toxicities to self‑medication and use of veterinary formulations: a FACT pharmacovigilance sub‑registry found that nearly half of patients in their series had used ivermectin for prevention or non‑documented COVID‑19 and 18/40 reported veterinary formulations, with neurological toxicity prominent among presentations [2]. National toxicology groups and poison centers reported surges in calls and emergency department presentations tied to non‑standard dosing, reflecting a misuse pattern rather than supervised, approved use [4] COVID-19.pdf" target="blank" rel="noopener noreferrer">[8].
**3. Types of adverse events seen and their plausibility**
The adverse events described clustered around neurological (ataxia, seizures, confusion), gastrointestinal (nausea, diarrhoea), and cardiovascular or hepatic signals in some pharmacovigilance reports; these are consistent both with high‑dose ivermectin toxicity and with known drug effects in vulnerable populations or in the context of drug interactions, and several case reports/series connected overdoses or massive inappropriate dosing to severe outcomes [2] [9] [10].
4. Why interpreting pharmacovigilance signals is difficult here
Spontaneous reporting systems are sensitive to media attention and behavioral change: increased publicity about ivermectin plausibly produced reporting spikes independent of true incidence increases, and many reports came from self‑medication or atypical formulations that fall outside the dosing assessed in randomized trials, creating heterogeneity between pharmacovigilance signals and controlled‑trial safety data [1] [3]. Systematic reviews of trials generally did not find a significant increase in adverse events in trial settings, underscoring the difference between supervised clinical dosing and the real‑world misuse that drove many pharmacovigilance cases [3] [6].
5. Systemic effects: burden on poison control, courts, and clinicians
The surge in ivermectin misuse translated into operational stress: poison centers and toxicology services recorded more exposures, professional societies issued cautions against off‑label prescribing, and clinicians faced legal and ethical pressure in a few high‑profile cases where courts or patients demanded ivermectin—circumstances that complicated stewardship and may have amplified reporting and treatment variability [4] [11].
6. Implications for signal detection and public health messaging
The ivermectin episode illustrated how off‑label promotion and availability of veterinary products can convert a pharmacologic agent with an established safety profile at indicated doses into a public‑health risk through misuse; pharmacovigilance systems therefore picked up an important, real signal about harm in the real world even while randomized evidence showed lack of benefit for COVID‑19 and mixed safety findings under trial conditions, prompting regulatory and professional warnings to prioritize clinician‑led decision‑making and better communication to the public [7] [10] [5].
Conclusion
Off‑label and veterinary use of ivermectin during the pandemic materially affected adverse‑event reporting and pharmacovigilance signals by producing more reports, more severe presentations linked to misuse and overdosing, and by exposing gaps between controlled‑trial safety and real‑world harm; these signals drove professional cautions and strained surveillance resources even as randomized trials failed to demonstrate COVID‑19 benefit, underscoring the need to interpret pharmacovigilance trends in the context of misuse, media effects and differing exposure profiles [2] [1] [3].