Ivermectin

This recommendation applies to acute COVID-19 in adults. Some of our recommendations vary according to the severity of COVID-19 illness. Definitions of the categories are based on the World Health Organization (WHO) criteria and can be viewed by clicking the plus (+) signs below.

RECOMMENDATION:  We recommend against using Ivermectin for treatment of patients with any severity of COVID-19 (strong recommendation). It has no benefit in reducing mortality, progression to mechanical ventilation and time to negative PCR and does not increase adverse effects.

DATE OF RECOMMENDATION: 06th October 2022

We do not recommend use of Ivermectin for treating COVID 19 illness (Strong recommendation)

Definition of mild:

  • Symptomatic (any acute COVID-19 related symptoms)
  • AND respiratory rate <24/min
  • WITHOUT pneumonia or hypoxia

Definition of moderate illness:

  • Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
  • AND respiratory rate ≤30/min
  • AND SpO2 ≥90% on room air

Definition of Severe illness

Pneumonia with ANY ONE of the following:

  • severe respiratory distress or respiratory rate >30/min
  • SpO2 <90% on room air
  • NO invasive or non-invasive respiratory support needed

Definition of critical:

  •  Requirement for high-level respiratory support: noninvasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
  • OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
  • OR sepsis
  • OR shock
Justification

The evidence from 20 randomized controlled trials (1–20), with 4140 participants suggests that Ivermectin does not improve mortality [RR 0.65, 95% CI 0.39, 1.09], progression to mechanical ventilation [RR 0.74, 95% CI 0.53, 1.04] or viral clearance in patients by day 7 with COVID-19 infection [RR 1.31, 95% I 0.95, 1.81]. At the doses used in these trials (median dose is 12 mg once daily orally) it does not have any major adverse events [RR 1.00, 95% CI 0.60, 1.67]. Multiple studies on Ivermectin in Covid-19 have been methodologically unsound with many retracted from peer reviewed literature, further clouding the data. (21,22) A stratified analysis of all-cause mortality in studies with low risk of bias showed no benefit with Ivermectin [RR 0.85, 95% CI 0.48, 1.50]

Currently, its use may distract from use of other therapies for which there is better evidence. Indiscriminate use might also reduce its availability for other conditions where its benefit is established, such as parasitic infections. Taking this into account, we recommend against use of ivermectin outside of a randomized controlled trial.

Evidence summary

Date of latest search: 07 June 2022.

Date of completion of Summary of findings table: 29th August 2022

Evidence synthesis team:  Harshdeep Acharya, Audrin Lenin, Jane Miracline John, Sherly Shulamite, Jisha Sara, Richard Kirubakaran, Priscilla Rupali and Bhagteshwar Singh.

Valuable assistance with performing the evidence synthesis was provided by the author team of an ongoing Cochrane systematic review: Maria Popp, Miriam Stegemann, Maria-Inti Metzendorf, Peter Kranke, Patrick Meybohm, Nicole Skoetz and Stephanie Weibel (23).

Summary of findings table

Explanations:

a.  Downgraded by one level for serious imprecision, due to small absolute number of events, and CIs include important potential benefit and important potential harm.

b.  Downgraded by one level for serious risk of bias. Due to Galan 2021 and Niaee 2021 having high risk of bias, and Gonzalez 2021 , Ravikirti 2021 , Abd Elsalam and Shahbaznejad 2021 having some concerns for risk of bias.

c.  Downgraded by one level for serious risk of bias, due to Abd Elsalam , Galan 2021, Ravikirti 2021Shahbaznejad and I-tech trial having some concerns for risk of bias.

d.  Downgraded by two levels for very serious risk of bias, due to Ahmed 2020 and Bukhari 2021 having high risk of bias and Bieber having some concerns for risk of bias for this outcome.

e.  Downgraded by one level for serious inconsistency, due to substantial heterogeneity (I-squared=64%) and visually some trials having point effect estimates very far from those of other trials.

f.  Downgraded by one level for serious imprecision, due to CIs overlapping no effect and inability to exclude important benefit.

g.  Downgraded by one level for serious risk of bias., due to Chaccour 2021, Chachar 2021, Rocha et. al etc having high risk of bias (accounts for 15% weightage).

h.  Downgraded by one level for serious imprecision, due to CIs overlapping including important potential benefit and important potential harm.

i.  Downgraded by one level for serious risk of bias, due to Gonzalez 2021 having high risk of bias

j.  Downgraded by one level for serious imprecision, due to CIs including important potential benefit and important potential harm.

Background

Ivermectin has been shown to inhibit the replication of SARS CoV2 in vitro; it binds and destabilises the viral protein and prevents it from entering the nucleus (24). However, the drug dosages used in these laboratory studies far exceed those that have been used for other conditions (25). Drug doses and levels required to achieve therapeutic effects in COVID-19 infection in humans based on these studies may be safe, but this has not been studied in clinical trials (26). An additional potential effect may be in modulating the immune system, though this is yet to be studied thoroughly in humans (27).

Although Ivermectin is generally well tolerated, adverse effects like dizziness, tachycardia, postural hypotension, diarrhoea, arthralgia, facial and peripheral oedema have been reported even with single doses as used in parasitic diseases (28). Encephalopathy with permanent disability has been reported when ivermectin has been used in the treatment of onchocerciasis or other parasitic diseases (28). It is predominantly metabolized in the liver (CYP3A4), which may lead to drug-drug interactions.

Due to lack of conclusive evidence from trials, World Health Organization recommends use of ivermectin only in clinical trials (29). Use continues widely, including self-medication, especially in low- and middle-income countries due to easy availability and low cost of the drug (30). Multiple trials on Ivermectin on covid-19 were retracted due to questionable methodology and lack of reliable data. (21,22)

This review aims to provide a summary of the available evidence from randomised clinical trials of ivermectin for treatment of acute COVID-19, for any dose or duration, so the Expert Working Group can provide a recommendation to guide clinicians and researchers regarding the appropriate use of this drug.

Methods

We used Cochrane rapid review methods. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Epistemonikos, and the COVID‐19‐specific resource www.covid‐nma.com, for studies of any publication status and in any language published from March 2020 up to 07th June 2022. We also reviewed reference lists of systematic reviews and included studies. We contacted researchers to identify unpublished and ongoing studies.

We included randomized controlled trials (RCTs) testing ivermectin treatment of any dose or duration in people with acute COVID‐19, whether suspected or confirmed. Trials were included if the intervention arm did not combine ivermectin with another experimental drug, and if the comparator arm did not include ivermectin (this could involve use of placebo, standard care, or other potentially active drugs). We excluded trials that did not report any outcomes that could provide usable data for the review, those which were quasi-randomized and those lacking a comparator arm.

We planned to extract data for the following outcomes, pre-defined by the Expert Working Group:

  • Critical (primary for this review):
    • Mortality (all-cause) – at 28-30 days, or in-hospital
    • Progression to:
      - Oxygen therapy
      - Ventilation: non-invasive or invasive
      - Critical or Intensive care (any reason)
    • Duration of hospitalization
    • Need for hospitalization (for out-patients)
    • Adverse events: all and serious
  • Important (secondary):
    • Time to clinical improvement
    • Time to negative PCR for SARS-CoV-2
    • Negative PCR for SARS-CoV-2 by day 7 post-enrolment
    • Complications of COVID-19:
      - Thrombotic events
      - Pulmonary function/fibrosis
      - Long covid/ post-covid sequalae
      - Secondary infections

Two reviewers independently assessed eligibility of search results. One reviewer extracted data from each included study and assessed risk of bias using the Cochrane Risk of bias (RoB) v2.0 tool. Data and RoB assessments were checked against a Cochrane systematic review team’s extractions and assessments (we used a consensus approach). In case of any discrepancies, the whole RoB assessment was scrutinised by the whole team for this review, to reach consensus.

We used RevMan 5.4 to perform meta‐analysis using a random‐effects model for outcomes where pooling of effect estimates was appropriate. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs).  We planned to explore heterogeneity in the effect on mortality using subgroup analysis comparing between trials, based on COVID-19 illness severity of participants included and risk of bias. We used the I2 statistic to measure residual heterogeneity. We used GRADE methodology to assess the certainty in the evidence and documented this in a ‘Summary of findings’ table using GradeProGDT.

Results

We included 20 trials involving 4140 participants, all of whom were adults, and 2122 of whom received ivermectin (1–20). Of these 11 studies are included in the previous recommendation and 9 new studies were added to update the evidence (21,22) While updating the evidence, we excluded 1 study (22) which was present in the previous analysis as it was retracted due to unreliable methodology. There were two trials each from, India, Iran, Pakistan, Brazil, and Mexico; one trial each was reported from Bangladesh, Colombia, Nigeria, Egypt, Israel, Italy, Argentina, Spain, Thailand, and Malaysia. Eleven were in hospitalized patients, four recruited out-patients only, one recruited both, and three did not report care setting. Disease severity, prevalence of comorbidities, and use of co‐interventions varied substantially between trials. The ‘Summary of characteristics of included trials’ table provides further details about the trials.

We found potential risks of bias across all domains; 12 of the 20 trials were at high risk of bias overall for at least one outcome. Risk of bias for each domain per trial is displayed alongside the Forest plots below. Studies excluded at full-text review are listed in the References section, with the reason provided in brackets (21,22,31–40).

The following comparisons were investigated in the trials. We compared outcomes for arms randomised to ivermectin vs. outcomes in arms with placebo, standard care, or agents considered inactive or ineffective against COVID-19. Where multiple arms contained ivermectin without another experimental agent, we combined results in those arms into a single ivermectin arm, but we did not double-count controls. Where another experimental agent undergoing investigation was combined with ivermectin, that trial arm was excluded from the analysis (e.g., doxycycline).

  • Ten trials (3–5,8,9,11,14,17,18,20) compared ivermectin vs. placebo (2358 participants)
  • Six [18;22-23;25-26;29] compared ivermectin vs. standard care (1244 participants)
  • One (1) compared ivermectin vs. placebo vs. a combination of ivermectin & doxycycline in three arms (72 participants; 24 participants in ivermectin & doxycycline arm excluded)
  • One (5) compared ivermectin vs. placebo vs. hydroxychloroquine in three arms (106 participants)
  • One (2) compared ivermectin vs. lopinavir/ritonavir (62 participants)
  • One (4) compared ivermectin vs. chloroquine or hydroxychloroquine (168 participants)

All-Cause-Mortality: Low certainty evidence from 9 RCTs (6,8,10,12,15,19,20) with 3052 participants shows that ivermectin may result in little to no difference in mortality [RR 0.65, 95%CI 0.39,1.09]. As the studies have some concerns and high risk of biases, a stratified analysis of the data was done based on ‘Risk of bias’. The trials (8,20) with Low risk of bias showed no difference in mortality in patients receiving Ivermectin vs no Ivermectin [RR 0.85, 95%CI 0.48,1.50]

Progression to mechanical ventilation: Low certainty evidence from 8 trials (6,11,12,15,16) with 3263 participants showed that Ivermectin may have little to no effect in the progression to mechanical ventilation [RR 0.74, 95%CI 0.53,1.04]. 5 of the 8 included studies have some concerns.

Negative PCR by day 7: Very low certainty evidence from 7 trials (1,3,11,13,17,20) with 828 participants for viral clearance at day 7 [RR 1.31, 95%CI 0.95,1.81] gives no impression of Ivermectin’s effect on viral clearance at Day 7. Of the 7 trials, 3 of them where of High Risk of bias, 3 of them had some concerns and only 1 trial with low risk of bias and had only 19% weightage. (Look at the forest plot).

Adverse events: Low certainty evidence from 10 RCTs (4,5,8,9,13,14,16,18–20) with 3187 participants shows that Ivermectin results in no significant adverse events RR 1.00, [95%CI 0.79,1.25].

Serious adverse events: Low certainty evidence from 4 RCTs (7,8,19,20) with 2352 participants shows that Ivermectin results in no significant serious adverse events [RR 1.00, 95%CI 0.60,1.67].

One trial reported a higher risk of discontinuation of ivermectin vs. placebo due to an adverse event (RR 2.97; 95% CI 1.10 to 8.02; 1 trial (8); 398 participants).

95% confidence intervals for pooled effect estimates for all of the following outcomes not included in the summary of findings table included potential benefit and potential harm from ivermectin: need for critical or intensive care (2 trials (6,11); 283 participants); discharge from hospital by day 10 post-enrolment (1 trial (11); 115 participants); deterioration by 2 points on 8-point clinical ordinal scale (1 trial (8); 398 participants); lack of fever on day 7 (1 trial (1); 36 participants); lack of symptoms on day 7 (1 trial (5); 50 participants); and thrombotic events (1 trial (7); 106 participants). We were unable to pool data for time to clinical improvement as they were not reported in a way that was amenable to meta-analysis (3 trials (4,8,9); 149 participants).

No comparative data could be extracted for risk of progression to oxygen therapy; need for hospitalisation in outpatients; or post-acute COVID-19 pulmonary function/fibrosis or other sequelae; or secondary infections.

Lack of uniform criteria for COVID-19 severity, substantial overlap, and lack of clear reporting of severity in the included trials prevented a meaningful subgroup analysis by severity.

Furthermore, a lack of within trial comparison prevented subgroup analysis by age, duration of symptoms or dose of ivermectin. In addition, data of safety and efficacy in specific subgroups such as pregnancy, children, liver, and kidney disease were not available in the trials included in the rapid review.

Summary of characteristics of included trials

CQ: Chloroquine; ECOG: Eastern Cooperative Oncology Group score; HCQ: Hydroxychloroquine; Lpv/Rtn: Lopinavir/Ritonavir; NEWS: National early warning score; RCT: Randomized control trial; RTPCR: Reverse transcription polymerase chain reaction; SoC: Standard of care

Forest Plot

1.  Mortality, stratified by risk of bias

2.  Progression to mechanical ventilation

3.  Negative PCR for SARS-CoV-2 by day 7

4.  Adverse events

5.  Serious adverse events

Evidence to decision

The methodology group for the evidence updating met on 29th March 2022 and the Voting for the recommendation by the Antiviral Expert working group completed on 09th May 2022 to consider Ivermectin as a treatment for COVID-19. A summary and then more detailed explanations of their judgements follow.

Problem

There is some evidence in the literature regarding use of ivermectin for treatment of COVID-19, but reports of trials and reviews are conflicting. Given current demand for effective treatments, examination of the evidence and a recommendation based on this is a priority. The PICO question now applies for all patients with COVID-19 (initial PICO was for hospitalised patients).

Desirable effects

The 95% CI for the pooled effect estimates for mortality, progression to mechanical ventilation and negative PCR at day 7 included the line of no difference (i.e.1); and the certainty of the evidence was low. This means that the desirable effects of ivermectin are not different from placebo or soc.

Undesirable effects

All 95% CI for the pooled effect estimates for adverse events and serious adverse events included the line of no difference (i.e.1); indicating that we do not know if adverse events are any different with ivermectin compared to placebo or the interventions compared in the trials.  This drug has been widely used and adverse effects at the dose used have not been reported commonly.

The group felt that in a patient with COVID, drug interactions are possible. For example, ivermectin can increase the concentration of warfarin, and one group member reported a case where a patient with COVID disease who was on warfarin and given ivermectin developed severe bleeding. The group also cautioned that use with dexamethasone can reduce ivermectin concentrations.

There is also the indirect risk of harm from relying on this treatment and not using treatments with better evidence, such as good supportive care.

Certainty of evidence

Using GRADE methods, the team rated the certainty of evidence as low for all outcomes in the Summary of findings table. The group agreed.

Values

The review included critical and important outcomes. Results were not reported for all, but results were pooled, and GRADE applied for four critical outcomes and one important outcome including death and adverse events.

Balance of effects

Since the certainty of evidence was low for desirable and undesirable effects of ivermectin, this means we do not know if ivermectin has an overall desirable effect compared to an undesirable effect when given to people with COVID disease.

Ivermectin used to be a part of the clinical protocol recommended by the Ministry of Health & Family Welfare for mild COVID-19 disease but is no longer recommended (41). The group discussed whether an intervention should be given if there is no observed benefit, as there is a risk to giving any intervention (see the section on Undesirable effects above).

Resources required

Cost of a dose, or a course as used in trials (up to 7 days of usual daily dose of up to 12mg) is low.

Certainty of evidence of required resources

Ivermectin is a low-cost treatment widely used in low- and middle-income settings for other conditions. We did not use published evidence on costs for this judgement, as ivermectin has been used extensively by the members of the expert working group for other conditions.

Cost effectiveness

None of the included trials assessed cost-effectiveness.

Equity

There is not enough information to make this judgement.

Acceptability

The group felt that many well-informed clinicians and patients may not accept an intervention for which the evidence for beneficial and adverse events were uncertain. However, in the context of a surge with few evidence-based therapeutic options, other clinicians and patients would feel a relatively safe, cheap oral drug might be acceptable in the absence of evidence for benefit. The group finally judged that ivermectin would probably be accepted, under such circumstances.

Feasibility

Evidence about feasibility was not specifically examined for COVID-19, but the group is aware of reports of mass-drug administration of ivermectin for other indications.

The group noted that it would be feasible to administer ivermectin in India for COVID-19 if it was found effective. However, we do not have data right now to suggest this. The group felt a recommendation for use would only detract from other interventions which have reported an unequivocal benefit.

Implementation considerations

Ivermectin is widely available, relatively inexpensive and has a low risk of adverse drug reactions. It may be used citing that lack of evidence of benefit is not evidence of lack of benefit. However, there are likely indirect harms. Its use may lead to a false sense of security. This could hamper close monitoring, and cause delay in the use of other interventions for which better evidence of benefit exists.

This recommendation is an update to the previous recommendation which was a conditional recommendation against the use of ivermectin in COVID-19.

Subgroup considerations

Our strong recommendation against use of ivermectin applies to all subgroups of patients with COVID-19.

Monitoring and evaluation

This strong recommendation against use of ivermectin may be revisited as evidence emerges. In addition to evidence of benefit, with its widespread use in India, there may be additional real-world reports regarding undesirable effects, which the group will monitor.

Research priorities

Further evidence for the use of Ivermectin in the treatment of COVID-19 needs to be generated from well-conducted randomized double-blind placebo-controlled trials which are adequately powered and have a low risk of bias. Utility in pre-specified patient sub-groups like mild, moderate, or severe infection, special populations (immunosuppressed, pregnant, children, comorbid conditions), and various phases of the illness will also need to be addressed. Safety of the dose required to achieve an antiviral/immunomodulatory effect also needs to be evaluated.

References
  1. Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis [Internet]. 2021 Feb 1 [cited 2022 Sep 30];103:214–6. Available from: https://www.sciencedirect.com/science/article/pii/S1201971220325066
  2. Babalola OE, Bode CO, Ajayi AA, Alakaloko FM, Akase IE, Otrofanowei E, et al. Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos. QJM Int J Med [Internet]. 2021 Nov 1 [cited 2022 Sep 30];114(11):780–8. Available from: https://doi.org/10.1093/qjmed/hcab035
  3. Bukhari KHS, Asghar A, Perveen N, Hayat A, Mangat SA, Butt KR, et al. Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease [Internet]. medRxiv; 2021 [cited 2022 Sep 30]. p. 2021.02.02.21250840. Available from: https://www.medrxiv.org/content/10.1101/2021.02.02.21250840v1
  4. Chaccour C, Casellas A, Blanco-Di Matteo A, Pineda I, Fernandez-Montero A, Ruiz-Castillo P, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine [Internet]. 2021 Feb 1 [cited 2022 Sep 30];32:100720. Available from: https://www.sciencedirect.com/science/article/pii/S2589537020304648
  5. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of Ivermectin in SARS-CoV-2/COVID-19 Patients. Int J Sci [Internet]. 2020 Oct 9 [cited 2022 Sep 30];9(09):31–5. Available from: https://www.ijsciences.com/pub/article/2378
  6. Galan LEB, Santos NM dos, Asato MS, Araújo JV, de Lima Moreira A, Araújo AMM, et al. Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with severe manifestations of SARS-CoV-2 infection. Pathog Glob Health [Internet]. 2021 May 19 [cited 2022 Sep 30];115(4):235–42. Available from: https://doi.org/10.1080/20477724.2021.1890887
  7. Gonzalez JLB, Gámez MG, Enciso EAM, Maldonado RJE, Palacios DH, Campos SD, et al. Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial [Internet]. medRxiv; 2021 [cited 2022 Sep 30]. p. 2021.02.18.21252037. Available from: https://www.medrxiv.org/content/10.1101/2021.02.18.21252037v1
  8. López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA [Internet]. 2021 Apr 13 [cited 2022 Sep 30];325(14):1426–35. Available from: https://doi.org/10.1001/jama.2021.3071
  9. Mohan A, Tiwari P, Suri T, Mittal S, Patel A, Jain A. Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial. Res Sq [Internet]. 2021 Feb 2 [cited 2022 Sep 30]; Available from: https://www.researchsquare.com
  10. Niaee MS, Gheibi N, Namdar P, Allami A, Zolghadr L. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial. Res Sq [Internet]. 2020 Nov 24 [cited 2022 Sep 30]; Available from: https://www.researchsquare.com
  11. Kirti R, Roy R, Pattadar C, Raj R. Ivermectin as a potential treatment for mild to moderate COVID-19: A double blind randomized placebo-controlled trial. Semantic Sch. 2021 Jan 9;
  12. Abd-Elsalam S, Noor RA, Badawi R, Khalaf M, Esmail ES, Soliman S, et al. Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: A randomized controlled study. J Med Virol [Internet]. 2021 [cited 2022 May 9];93(10):5833–8. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.27122
  13. Biber A, Mandelboim M, Harmelin G, Lev D, Ram L, Shaham A, et al. Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial [Internet]. medRxiv; 2021 [cited 2022 Sep 30]. p. 2021.05.31.21258081. Available from: https://www.medrxiv.org/content/10.1101/2021.05.31.21258081v1
  14. Buonfrate D, Chesini F, Martini D, Roncaglioni MC, Ojeda Fernandez ML, Alvisi MF, et al. High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial [Internet]. Rochester, NY; 2021 [cited 2022 Sep 30]. Available from: https://papers.ssrn.com/abstract=3918289
  15. Shahbaznejad L, Davoudi A, Eslami G, Markowitz JS, Navaeifar MR, Hosseinzadeh F, et al. Effects of Ivermectin in Patients With COVID-19: A Multicenter, Double-blind, Randomized, Controlled Clinical Trial. Clin Ther. 2021 Jun;43(6):1007–19.
  16. Vallejos J, Zoni R, Bangher M, Villamandos S, Bobadilla A, Plano F, et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis. 2021 Jul 2;21(1):635.
  17. Manomaipiboon A, Pholtawornkulchai K, Pupipatpab S, Suraamornkul S. Efficacy and safety of ivermectin in the treatment of mild-to-moderate COVID-19 infection: A randomized, double blind, placebo, controlled trial | Research Square. Res Sq [Internet]. 2022 Feb 2 [cited 2022 Sep 30]; Available from: https://www.researchsquare.com/article/rs-1290999/v1
  18. Rocha C de la, Cid-Lopez MA, Venegas-Lopez BI, Gómez-Mendez SC, Sánchez-Ortiz A, Pérez-Ríos AM. Ivermectin compared with placebo in the clinical evolution of Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial. Res Sq [Internet]. 2022 May 9; Available from: https://www.researchsquare.com/article/rs-1640339/v1
  19. Lim SCL, Hor CP, Tay KH, Mat Jelani A, Tan WH, Ker HB, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial. JAMA Intern Med [Internet]. 2022 Apr 1 [cited 2022 Jul 29];182(4):426–35. Available from: https://doi.org/10.1001/jamainternmed.2022.0189
  20. Reis G, Silva EASM, Silva DCM, Thabane L, Milagres AC, Ferreira TS, et al. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med [Internet]. 2022 May 5 [cited 2022 Aug 29];386(18):1721–31. Available from: https://doi.org/10.1056/NEJMoa2115869
  21. Elgazzar A, Eltaweel A, Youssef SA, Hany B, Hafez M, Moussa H. Efficacy and Safety of Ivermectin for Treatment and prophylaxis of COVID-19 Pandemic. Res Sq [Internet]. 2020 Dec 28 [cited 2022 Sep 30]; Available from: https://www.researchsquare.com
  22. Pott-Junior H, Paoliello MMB, Miguel A de QC, da Cunha AF, de Melo Freire CC, Neves FF, et al. RETRACTED: Use of ivermectin in the treatment of Covid-19: A pilot trial. Toxicol Rep [Internet]. 2021 Jan 1 [cited 2022 Sep 30];8:505–10. Available from: https://www.sciencedirect.com/science/article/pii/S2214750021000445
  23. Popp M, Stegemann M, Metzendorf MI, Gould S, Kranke P, Meybohm P, et al. Ivermectin for preventing and treating COVID‐19. Cochrane Database Syst Rev [Internet]. 2021 [cited 2022 Sep 30];(4). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015017/full
  24. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res [Internet]. 2020 Jun 1 [cited 2022 Sep 30];178:104787. Available from: https://www.sciencedirect.com/science/article/pii/S0166354220302011
  25. Schmith VD, Zhou J (Jessie), Lohmer LRL. The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID‐19. Clin Pharmacol Ther [Internet]. 2020 Oct [cited 2022 Sep 30];108(4):762–5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267287/
  26. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002 Oct;42(10):1122–33.
  27. Zhang X, Song Y, Ci X, An N, Ju Y, Li H, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res [Internet]. 2008 Nov 1 [cited 2022 Sep 30];57(11):524–9. Available from: https://doi.org/10.1007/s00011-008-8007-8
  28. Chandler RE. Serious Neurological Adverse Events after Ivermectin—Do They Occur beyond the Indication of Onchocerciasis? Am J Trop Med Hyg [Internet]. 2017 Dec 4 [cited 2022 Sep 30];98(2):382–8. Available from: https://www.ajtmh.org/view/journals/tpmd/98/2/article-p382.xml
  29. Therapeutics and COVID-19: living guideline [Internet]. [cited 2022 Feb 11]. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2022.1
  30. Molento MB. COVID-19 and the rush for self-medication and self-dosing with ivermectin: A word of caution. One Health Amst Neth. 2020 Dec;10:100148.
  31. Podder CS, Chowdhury N, Sina MI, Haque WMMU. Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC J Med Sci [Internet]. 2021 Apr 5 [cited 2022 Sep 30];14(2):11–8. Available from: http://www.imcjms.com/registration/journal_full_text/353
  32. Shoumann WM, Hegazy AA, Nafae RM, Ragab MI, Samra SR. Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomised Clinical Trial. JCDR [Internet]. 2021 Feb [cited 2022 Sep 30];15(2):OC27–32. Available from: https://jcdr.net/article_fulltext.asp?issn=0973-709x&year=2021&volume=15&issue=2&page=OC27&issn=0973-709x&id=14529
  33. Rezai M. IRCT | Effectiveness of Ivermectin in the Treatment of Coronavirus Infection in Patients admitted to Educational Hospitals of Mazandaran in 2020 [Internet]. [cited 2022 Sep 30]. Available from: https://en.irct.ir/trial/49174
  34. Fawaz M, RaaD H. In vivo use of ivermectin (IVR) for treatment for corona virus infected patients (COVID-19): a randomized controlled trial [Internet]. [cited 2022 Sep 30]. Available from: http://www.chictr.org.cn/showproj.aspx?proj=54707
  35. Chahla RE, Ruiz LM, Ortega ES, Morales MF, Barreiro F, George A, et al. A Randomized Trial - Intensive Treatment Based in Ivermectin and Iota-Carrageenan as Pre-Exposure Prophylaxis for Covid- 19 in Healthcare Agents [Internet]. medRxiv; 2021 [cited 2022 Sep 30]. p. 2021.03.26.21254398. Available from: https://www.medrxiv.org/content/10.1101/2021.03.26.21254398v1
  36. Chowdhury ATMM, Shahbaz M, Karim MR. A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients. 2020 Jul 14 [cited 2022 Sep 30]; Available from: https://www.researchsquare.com
  37. Hashim HA, Maulood MF, Rasheed AM, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in Baghdad, Iraq [Internet]. medRxiv; 2020 [cited 2022 Sep 30]. p. 2020.10.26.20219345. Available from: https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1
  38. Krolewiecki A, Lifschitz A, Moragas M, Travacio M, Valentini R, Alonso DF, et al. Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial [Internet]. Rochester, NY; 2020 [cited 2022 Sep 30]. Available from: https://papers.ssrn.com/abstract=3714649
  39. Okumuş N, Demirtürk N, ÇETİNKAYA RA, GÜNER R, Avcı İY, ORHAN S. Evaluation of the Effectiveness and Safety of Adding Ivermectin to Treatment in Severe COVID-19 Patients. Res Sq [Internet]. 2021 Feb 24 [cited 2022 Sep 30]; Available from: https://www.researchsquare.com
  40. Mahmud R, Rahman MM, Alam I, Ahmed KGU, Kabir AKMH, Sayeed SKJB, et al. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. J Int Med Res. 2021 May;49(5):3000605211013550.
  41. AIIMS C. Clinical guidance for Management of Adult COVID-19 Patients [Internet]. AIIMS NEW. [cited 2022 Sep 30]. Available from: https://aiims.edu/en/notices/notices.html?id=11611
Citation

Covid Management Guidelines India Group - Anti-viral Working Group. Ivermectin. Covid Guidelines India; Published online on Oct 06th, 2022; URL:  https://indiacovidguidelines.org/ivermectin-2/ (date<>).

Ivermectin – (Previous Recommendations)