Ivermectin

Last review completed on
August 11th, 2021

Ivermectin is an anthelminthic that has some anti-viral properties. There is in vitro evidence of activity against SARS-CoV-2 in infected Vero-hSLAM cells with high concentrations of the drug. There are mixed results in clinical trials. A recently published Cochrane Review did not determine evidence to support the use of ivermectin for COVID-19. Authors concluded that based on very low to low certainty evidence they were uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19.

The NIH COVID-19 Treatment Guidelines Panel states there is insufficient data to recommend for or against use of ivermectin for the treatment of COVID-19. (last updated 2/11/21, accessed 8/11/21). FDA issued a warning concerning possible inappropriate use of ivermectin products intended for animals as an attempt to self-medicate for the treatment of COVID-19. Conversely, Front Line COVID-19 Critical Care Alliance (FLCCC) supports an A-I recommendation for use of ivermectin in both prophylaxis and treatment of all phases of COVID-19 (last updated 1/12/21, accessed 8/11/21). 

Recommendation

There is insufficient data at this time to recommend its use in COVID-19. There are studies demonstrating its role in prophylaxis and treatment of COVID-19, however the majority of these studies are not yet peer reviewed. These studies have limitations including small sample sizes, various concomitant medications used, and various doses and schedules of ivermectin used. In addition, a large redacted study has had an effect on subsequent meta-analyses, adding confusion to the cumulating literature. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.

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Clinical Circumstances

Ivermectin 0.2mg/kg orally once daily for 1-2 days (rounded to the nearest 3mg tablet size) is recommended for patients with COVID-19 who are receiving dexamethasone and who have lived or travelled in a strongyloides endemic area.  Contraindications for this use are pregnancy, Loa Loa infection, and weight <15kg. 

Medication-specific Consideration

Based on the current literature, what dosing is recommended?

Ivermectin 0.2-0.4mg/kg given orally daily for 1-5 days.

Is treatment currently available for use in our system, and if so are shortages anticipated? Are there currently restrictions or other barriers?

Yes, ivermectin is available to order. There are no current shortages.  If its use in COVID-19 increases in the U.S., there could be future supply constraints. However, the existence of two different manufacturers (one sells brand, one sells generic) that sell the drug to M Health Fairview helps mitigate that barrier. No other barriers.

Please consider use in special populations (pregnancy, immunosuppressed, kidney or liver disease, etc.) and outline any concerns below.

  • Pregnancy: Ivermectin has historically not been contraindicated in pregnancy. Animal studies raised concerns about ivermectin use in early stages of pregnancy (prior to 10 weeks gestation). A 2020 systematic review was unable to establish a causal relationship between ivermectin use and poor maternal or fetal outcomes due to the quality of evidence. 2020 guidelines of parasite infections recommend a benefit risk analysis in pregnant patients, prefer other agents for less severe infections, and prefer ivermectin for more severe infections. Pregnant patients were excluded from some of the studies in COVID-19 included in this review. Ultimately there is insufficient evidence to establish the safety of ivermectin in pregnancy.
     
  • Children <2 years old or <15kg: American Academy of Pediatrics cautions against using ivermectin in this population due to a less developed blood-brain barrier compared to older pediatric patients and an increased risk for CNS effects
     
  • Kidney: no dosage adjustments
     
  • Liver: no dosage adjustments
     
  • Patients taking warfarin: Ivermectin may increase PT and enhance the anticoagulant effect of warfarin
Level of Evidence
= Supporting use article = Neutral Article  = Contradicting use article

Step 1 - In vitro SARS CoV-1/2 and MERS-CoV

 Step 2 - In vivo MERS-CoV Step 3 - In vivo SARS CoV-2





Contradicting Use article
Contradicting Use article

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Major Peer-reviewed Studies

Level 6: Systematic review and meta-analysis articles listed below Peer-reviewed systematic review in the treatment in the treatment and prophylaxis of COVID-19:

  1. Contradicting Use article Popp M, Stegemann M, Metzendorf MI, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. 2021;7:CD015017. Published 2021 Jul 28. doi:10.1002/14651858.CD015017.pub2
    • ​​Contraindicating: No evidence to support its use. Authors concluded that based on very low to low certainty evidence they were uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19.
    • Inpatient treatment: ivermectin vs placebo or standard of care
      • Mortality: risk ratio 0.60; 95% CI 0.14 to 2.51; 2 studies, 185 participants; very-low evidence
      • Clinical worsening up to day 28 assessed as need for invasive mechanical ventilation: risk ratio 0.55; 95% CI 0.11 to 2.59; 2 studies, 185 participants; very-low evidence
      • Viral clearance at day seven: risk ratio 1.21; 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low certainty evidence
    • Outpatient treatment: ivermectin vs placebo or standard of care 
      • Mortality up to 28 days: risk ratio 33, 95% CI 0.01 to 8.05; 2 studies, 422 participants, very low certainty evidence
      • Viral clearance at day seven: risk ratio 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low‐certainty evidence
      • Number of participants with symptoms resolved up to 14 days (risk ratio 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low‐certainty evidence)
      • No study reported hospital admission or quality of life up to 14 days
    • ​​​​​​​​​​​​​​Prevention: ivermectin vs no treatment
      • Mortality up to 28 days: 0 participants died; 1 study, 304 participants; very low certainty evidence
      • ​​​​​​​Mortality was only outcome eligible for primary analysis, results for development of COVID-19 symptoms and adverse events up to 14 days were included in a secondary analysis due to high risk of bias

Level 5: Random Controlled Trial SARS CoV-2 articles listed below Peer-reviewed randomized controlled trials in the treatment of COVID-19:

  1.  Contradicting Use article Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms.
    López-Medina E, López P, Hurtado IC, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial [published online ahead of print, 2021 Mar 4]. JAMA. 2021;10.1001/jama.2021.3071.
  2. Demonstrated statistically significant impacts in time to recovery or hospital length of stay. Spoorthi V, S.S. (2020).
    Utility of Ivermectin and Doxycycline combination for the treatment of SARS-CoV2. International Archives of Integrated Medicine 7, 177-182.
  3. Demonstrated statistically significant decrease in viral load, days of anosmia and cough.
    Chaccour, C., Casellas, A., Blanco-Di Matteo, A., Pineda, I., Fernandez-Montero, A., Castillo, P.R., Richardson, M.-A., Mateos, M.R., Jordan-Iborra, C., and Brew, J. (2020). The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with mild COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial.
  4. Near statistically significant decrease in time to recovery. 
    Chowdhury, A.T.M.M., Shahbaz, M., Karim, M.R., Islam, J., Guo, D., and He, S. (2020). A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients

Level 4: Observational SARS CoV-2 articles listed below Peer-reviewed observational controlled trials in the prophylaxis of COVID-19:

  1.   Demonstrated statistically significant reduction in transmission rates (N = 2052).
    Alam, M., R, M., Pf, G., Md, M.Z., S, S., and Ma, C. (2020). Ivermectin as Pre-exposure Prophylaxis for COVID 19 among Healthcare Providers in a Selected Tertiary Hospital in Dhaka An Observational Study. European Journal of Medical and Health Sciences.
  2. Bernigaud C, Guillemot D, Ahmed-Belkacem A, et al. Bénéfice de l’ivermectine : de la gale à la COVID-19, un exemple de sérendipité. Ann Dermatol Venereol. 2020;147(12):A194.
  3. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin. Int J Antimicrob Agents. 2021;57(1):106248.

 

    List of major peer-reviewed studies providing context for therapy

    Level 1: In vitro SARS CoV-1/2 and MERS-CoV articles listed below In Vitro Studies

    1. Supporting Use article Mastrangelo E, Pezzullo M, De Burghgraeve T, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012; 67:1884-94. PMID: 22535622 DOI:10.1093/jac/dks147
    2. Supporting Use article Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res. 2020. PMID: 32134219 DOI: 10.1016/j.antiviral.2020.104760.
    3. Supporting Use article Varghese FS, Kaukinen P, Glasker S, et al. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Res. 2016. 126:117-24. PMID: 26752081 DOI: 10.1016/j.antiviral.2015.12.012.
    4. Supporting Use article Azeem S, Ashraf M, Rasheed MA, et al. Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus. Pak J Pharm Sci. 2015; 28:597-602. PMID: 25730813.
    5. Supporting Use article Tay MY, Fraser JE, Chan WK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res. 2013; 99:301-6. PMID: 23769930 DOI: 10.1016/j.antiviral.2013.06.002. 
    6. Supporting Use article Caly L, Druce JD, Catton MG et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020; 178:104787 [Epub]. PMID: 32251768.
    7. Schmith VD, Zhou JJ, Lohmer LR. The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther. 2020; May 7. PMID: 32378737.

    List of pre-peer reviewed/pre-publication studies providing context for therapy

    Level 6: Systematic review and meta-analysis articles listed below Meta-analysis of ivermectin in the prophylaxis of COVID-19: 

    1.  Kory PM, Meduri GUM, Iglesias J, et al. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. doi:10.31219/osf.io/wx3zn.
      1. Summary of 4 OCTs: odds ratio for symptomatic infection, ivermectin vs control: 0.073 (95% CI: 0.044 to 0.123); z-value -9.900; p-value 0.000
      2. Summary of 3 RCTs: odds ratio for symptomatic infection, ivermectin vs control: 0.079 (95% CI: 0.047 to 0.135); z-value -9.385, p-value 0.000

    Level 6: Systematic review and meta-analysis articles listed below Meta-analysis of ivermectin in treatment of COVID-19:

    1.  Kory PM, Meduri GUM, Iglesias J, et al. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. doi:10.31219/osf.io/wx3zn.
      1. Outcome of time to clinical recovery: combined result of 7 controlled trials significantly favored ivermectin over control
      2. Outcome of mortality: combined result of 4 OCTs and 6 RCTs significantly favored ivermectin
    2.  Andrew Hill, Ahmed Abdulamir, Sabeena Ahmed et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection, 19 January 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-148845/v1]
      1. This meta-analysis of 18 RCTs in 2282 patients showed a 75% improvement in survival, faster time to clinical recovery and signs of a dose-dependent effect of viral clearance for patients given ivermectin versus control treatment.

    Level 6: Systematic review and meta-analysis articles listed below Systematic review of ivermectin in treatment of COVID-19: 

    1.  Kalfas, S., Visvanathan, K., Chan, K., and Drago, J. THE THERAPEUTIC POTENTIAL OF 755 IVERMECTIN FOR COVID-19: A REVIEW OF MECHANISMS AND EVIDENCE. 756 medRxiv. 2020. Preprint
      1. Positive mortality benefit, reduced time to clinical recovery, reduced 71 incidence of disease progression and decreased duration of hospital admission were 72 reported in patients across all stages of clinical severity

    Level 5: Random Controlled Trial SARS CoV-2 articles listed below Randomized controlled trials in the prophylaxis of COVID-19:

    1. Supportive: Demonstrated statistically significant reduction in transmission rates
      1.  Chala (2020). Prophylaxis Covid-19 in Healthcare Agents by Intensive Treatment With Ivermectin and Iota-carrageenan (Ivercar-Tuc). ClinicalTrials.gov NCT04701710.
      2.  Shouman, W. (2020). Use of Ivermectin as a Prophylactic Option in Asymptomatic Family Close Contact for Patient with COVID-19. ClinicalTrials.gov.

        * Please note that a Research Square pre-print by Elgazzar et al was previously included in this section in the March 2021 EBM review, but the pre-print has since been withdrawn by Research Square on 14 July, 2021 due to an expression of concern communicated directly to their staff.

    Level 5: Random Controlled Trial SARS CoV-2 articles listed below Randomized controlled trials in the treatment of COVID-19:

    1. Demonstrated statistically significant reduction in mortality
      1.  Morteza Shakhsi Niaee, Nematollah Gheibi, Peyman Namdar et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial, 24 November 2020, PREPRINT (Version 1) available at Research Square.
      2.  Ravikirti, Roy, R., Pattadar, C., Raj, R., Agarwal, N., Biswas, B., Majhi, P.K., Rai, D.K., Shyama, Kumar, A., and Sarfaraz, A. (2021). Ivermectin as a potential treatment for mild to moderate COVID-19 – A double blind randomized placebo-controlled trial. medRxiv, 2021.2001.2005.21249310.

        * Please note that a Research Square pre-print by Elgazzar et al was previously included in this section in the March 2021 EBM review, but the pre-print has since been withdrawn by Research Square on 14 July, 2021 due to an expression of concern communicated directly to their staff.
         
    2. Demonstrated statistically significant impacts in time to recovery or hospital length of stay
      1.  Hashim, H.A., Maulood, M.F., Rasheed, A.M., Fatak, D.F., Kabah, K.K., and Abdulamir, A.S. (2020). Controlled randomized clinical trial on using Ivermectin with Doxycycline for 739 treating COVID-19 patients in Baghdad, Iraq. medRxiv
      2.  Mahmud, R. (2020). A Randomized, Double-Blind Placebo Controlled Clinical Trial of Ivermectin plus Doxycycline for the Treatment of Confirmed Covid-19 Infection

    Level 4: Observational SARS CoV-2 articles listed below Observational controlled trials in the prophylaxis of COVID-19:

    1. Supportive: Demonstrated statistically significant reduction in transmission rates
      1.  Behera, P., Patro, B.K., Singh, A.K., Chandanshive, P.D., Ravikumar, S., Pradhan, S.K., Pentapati, S.S.K., Batmanabane, G., Padhy, B.M., and Bal, S. (2020). Role of ivermectin in the prevention of COVID-19 infection among healthcare workers in India: A matched case control study. medRxiv.
      2.  Carvallo, H.E., Roberto, H., Psaltis, A., and Veronica, C. (2020b). Study of the Efficacy and Safety of Topical Ivermectin+ Iota-Carrageenan in the Prophylaxis against COVID-19 in Health Personnel.

    Level 4: Observational SARS CoV-2 articles listed below Observational controlled trial

    1. Pilot observational study comparing efficacy of add-on ivermectin in pts with mild to moderate COVID-19 (not peer reviewed- Gorial FI, Mashhadani S, Sayaly HM, et al. Effectiveness of ivermectin as add-on therapy in COVID-19 management (pilot trial). medRxiv. Posted July 8, 2020. Preprint.

    Level 4: Observational SARS CoV-2 articles listed below Observational controlled trials in the treatment of COVID-19

    1. Demonstrated statistically significant reductions in mortality
      1.  Khan, M.S.I., Khan, M.S.I., Debnath, C.R., Nath, P.N., Mahtab, M.A., Nabeka, H., Matsuda, S., and Akbar, S.M.F. (2020). Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19. Archivos de Bronconeumología
      2.  Portmann-Baracco, A., Bryce-Alberti, M., and Accinelli, R.A. (2020). Antiviral and Anti Inflammatory Properties of Ivermectin and Its Potential Use in Covid-19. Arch Bronconeumol.
      3.  Rajter, J.C., Sherman, M.S., Fatteh, N., Vogel, F., Sacks, J., and Rajter, J.J. (2020). Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID-19 (ICON study). Chest.
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