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data and “real world” data sources need careful evaluation using these key principles of review: expert peer review of evidence, assessment of errors in reporting, assessment of due scientific diligence, and careful consideration of confounders. These principles have not been applied to this data. • This observational data is much lower quality evidence compared with randomized trials (which also can vary in quality and require assessment). There is variability in assessment of infection rates and outcome reporting at a population level, as well as confounding. • Multiple sources suggest the infection rate and death toll of COVID-19 in India in general, and Uttar Pradesh in particular, has been underestimated and current transmission is likely lower because of post infection immunity in survivors given prior waves of the pandemic o India’s death toll (and associated case counts) is estimated to be at least 7-13X higher than reported, suggesting actual population infection rates have been 60- 70%, confirmed by seroprevalence data. Multiple resources indicate that cremations outstripped official death estimates considerably in this area. o A preprint analysis of excess mortality for India related to COVID-19 (which found up to 2% of the population died up to June, 2021) had to omit data from Uttar Pradesh because of significant reporting irregularities (including districts that reported NO deaths for months) o Public health seroprevalence data reported by the Center for Global Development suggested extreme underreporting of cases and deaths in Uttar Pradesh, and Indian Council of Medical Research data (reported by press release) showed 71% seroprevalence in Uttar Pradesh in spite of only 29% initial dose vaccinated in July. It is also noted that many districts in India used ivermectin over a period in which the evidence was less clear, based on national guidelines, so regions cannot be compared based on use or non-use. Ivermection and hydroxychloroquine have recently been removed from the national COVID-19 guidelines in India for lack of efficacy. In summary, this would suggest Uttar Pradesh had a devastating prior COVID-19 surge with high case rates and significant uncounted mortality, with current evidence of partial population immunity in people who survived COVID-19 infection and increasing numbers of vaccinated people. Major COVID-19 Guidelines and Manufacturers Statement Do Not Support Ivermectin Use, in Part Given Safety Concerns As summarized in the Cochrane review, national and international guidelines regarding the use of ivermectin for the treatment or prevention of COVID‐19 have been developed over the past 12 months. Recommendations from the WHO, updated 31 March 2021 (WHO 2021b); European Medicines Agency, updated 22 March 2021 (EMA 2021); Infectious Diseases Society of America, updated 13 February 2021 (IDSA 2021); and the COVID Management Guidelines India Group, updated 15 May 2021 (COVID Guidelines India 2021), concur that ivermectin should only be used for treatment of COVID‐19 in the context of clinical trials. The EMA additionally advises against the use of ivermectin for prophylaxis outside RCTs (EMA 2021). The US NIH guidance updated on 11February 2021 describes 'insufficient data' to permit a recommendation for or against the use of ivermectin for the treatment of COVID‐19 (NIH 2021). In addition it is notable that Merck, the manufacturers of ivermectin, have concluded that there is: • “No scientific basis for a potential therapeutic effect against COVID-19 from pre-clinical studies; • No meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19 disease, and; • A concerning lack of safety data in the majority of studies.” Furthermore, Merck states that “We do not believe that the data available support the safety and efficacy of Ivermectin beyond the doses and populations indicated in the regulatory agencyapproved prescribing information.” As noted in the SAG review that follows, the product monograph for Stromectol® oral ivermectin tablets reports that no fatalities have been observed in humans due to overdose of medicalgrade ivermectin (Merck Canada Inc., 2020). Consumption of veterinary-grade ivermectin formulations, which contain ingredients not used in human medicines, most commonly results in rash, contact dermatitis, edema, headache, dizziness, asthenia, nausea, vomiting, and diarrhea (Merck Canada Inc., 2020). The US Food & Drug Administration warns that “even the levels of ivermectin for approved human uses can interact with other medications, like blood-thinners. You can also overdose on ivermectin, which can cause nausea, vomiting, diarrhea, hypotension (low blood pressure), allergic reactions (itching and hives), dizziness, ataxia (problems with balance), seizures, coma and even death.” They also warn that the doses used for animals are often highly concentrated because they are intended for use in large animals, and that these doses can be highly toxic for humans. Furthermore, many of the inactive ingredients found in products for animals are not intended for use in humans. Several high quality randomized controlled trials are being conducted to further study the use of ivermectin for COVID-19; this review and recommendations will be updated as new evidence comes to light. Prescribing 

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