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ivermectin as a treatment for COVID-19? 3. Are there risks associated with the use of ivermectin for prophylaxis or treatment of COVID-19? 4. Does available data on utilization of accessible ivermectin products in Alberta suggest that it is being used in COVID-19? Context • Ivermectin is a well-characterized drug that is used to treat parasitic infections in both humans and animals. Laboratory based studies have shown ivermectin can inhibit SARS-CoV-2 (the virus causing COVID-19) replication, raising the possibility that ivermectin may have a role in COVID-19 prophylaxis or treatment. • Statements regarding ivermectin as a potential “miracle cure” for COVID-19 from Dr. Pierre Kory of the Front-Line Covid-19 Critical Care Alliance have attracted much attention on social media (e.g. NewsNOW from FOX, 2020). Subsequently, cautionary statements regarding the potential effectiveness of ivermectin were made by the FDA and NIH. Many drugs that show promise in laboratory based studies are not found to be effective in patients (Hay et al., 2014). • The World Health Organization living guidelines for COVID-19 therapy from the British Medical Journal do not recommend ivermectin (Siemeniuek et al, 2020), and recently updated guidelines from the National Institutes of Health (as of 14 January 2021) state that there is insufficient evidence to “recommend either for or against ivermectin as a treatment for COVID-19” (National Institutes of Health, 2021). An ongoing analysis of RCT data rates ivermectin trials as having "very low" certainty evidence. • As was seen with the interest in hydroxychloroquine use in the early stages of the COVID-19 pandemic, there are many ongoing clinical studies (of varying quality) to assess the effectiveness of ivermectin as a treatment for COVID-19. • There are anecdotal reports of prescribers and patients in Alberta seeking medical-grade and veterinary-grade ivermectin for off-label use with which to treat COVID-19. Care providers in South America also show great enthusiasm for ivermectin as a treatment for COVID-19, despite the limited evidence base. Key Messages from the Evidence Summary • Ivermectin has been shown to inhibit viral replication in vitro, but at concentrations that may be unattainable with human therapeutic doses. Vero cells (a non-human cell line) infected with SARS-CoV-2 and treated with 5 μmol/L ivermectin at 2 hours post-infection showed a 5000X reduction in viral replication compared to untreated controls. However, the 100% inhibitory concentrations of ivermectin needed in vitro are approximately 50-55X higher than the maximum plasma concentration of ivermectin after an oral dose of 12 mg in adults. • Studies evaluating ivermectin treatment are of inadequate quality for definitive assessment of ivermectin use in prophylaxis and therapy, with many studies involving incompletely described use of multiple other medications meant to manage symptoms and limit viral replication, inappropriate study design, 6 Last revised: February 2, 2021 inadequate controls, short follow-up length, performance bias, small sample sizes and high risk of bias from confounding factors. • Ivermectin has a favourable pharmacokinetic and safety profile when used according to label directions. Adverse events ascribed to ivermectin reported in the primary literature or the meta-analyses were non-severe and aligned with the side effects listed on the product monograph when used according to the medication label. The product monograph from Merck Canada advises against using ivermectin in pregnant women, children under 15 kg, and adults over 65 as the safety evidence is limited or has not yet been established however states that no fatalities or toxicity have been reported due to ivermectin overdose. • A formal critical appraisal of the identified meta-analyses and included primary literature was undertaken. The meta-analyses were judged to be of critically low quality (Lawrie, 2021); low quality (Hill et al., preprint), and moderate quality (Padhy et al., 2020) after AMSTAR-2 assessment. The primary studies were assessed using the Downs & Black checklist. The majority of primary studies were assessed as fair quality (ie. they received a score of 14-18 out of a possible 32). • For use in prophylaxis, the one meta-analysis containing two RCTs and two observational studies (Lawrie, 2021) was judged as critically low quality by AMSTAR-2 assessment; thus, the findings were not included in this review. The primary evidence was extracted and summarized with an additional observational study that was retrieved in the database search. All four studies show a significant reduction in COVID-19 infection in the intervention group; however, each study was at high risk of bias from confounding prevention behaviors. • One preprint case control study in health care workers (Behera et al., preprint) suggested that ivermectin was independently associated with 73% reduced odds of COVID-19 infection (OR 0.27, 95%CI 0.15-0.51) and a history of exercise for more than one hour (as a proxy measure for inadequate social distancing) was an independent risk factor for COVID-19 infection (3.06 CI 1.18-7.93). In this study, HCWs were offered HQ prophylaxis after exposures for the initial period, and then ivermectin prophylaxis was offered, however, other workplace prevention measures instituted and changed, and 

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