Ivermectin: The Facts from the National Institutes of Health.

Updated: Dec 20, 2021


Ivermectin

Drug Info / Clinical Data

Last Updated: February 11, 2021


Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug that is used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies. It is also being evaluated for its potential to reduce the rate of malaria transmission by killing mosquitoes that feed on treated humans and livestock.

For these indications, ivermectin has been widely used and is generally well tolerated.

Ivermectin is not approved by the FDA for the treatment of any viral infection. (ref: footnotes 1 - 4)


Proposed Mechanism of Action and Rationale for Use in Patients With COVID-19

Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host’s antiviral response.(4,5) In addition, ivermectin docking may interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to the human cell membrane.6 Ivermectin is thought to be a host-directed agent, which may be the basis for its broad-spectrum activity in vitro against the viruses that cause dengue, Zika, HIV, and yellow fever.(4,7-9) Despite this in vitro activity, no clinical trials have reported a clinical benefit for ivermectin in patients with these viruses.


Some studies of ivermectin have also reported potential anti-inflammatory properties, which have been postulated to be beneficial in people with COVID-19.10-12 Some observational cohorts and clinical trials have evaluated the use of ivermectin for the prevention and treatment of COVID-19. Data from some of these studies can be found in Table 2c.

Recommendation There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of ivermectin for the treatment of COVID-19. 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.


Rationale Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in cell cultures.13 However, pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans.14,15 Even though ivermectin appears to accumulate in the lung tissue, predicted systemic plasma and lung tissue concentrations are much lower than 2 µM, the half-maximal inhibitory concentration (IC50) against SARS-CoV-2 in vitro.16-19 Subcutaneous administration of ivermectin 400 µg/kg had no effect on SARS-CoV-2 viral loads in hamsters. However, there was a reduction in olfactory deficit (measured using a food-finding test) and a reduction in the interleukin (IL)-6:IL-10 ratio in lung tissues.20 Since the last revision of this section of the Guidelines, the results of several randomized trials and retrospective cohort studies of ivermectin use in patients with COVID-19 have been published in peer-reviewed journals or have been made available as manuscripts ahead of peer review. Some clinical studies showed no benefits or worsening of disease after ivermectin use,(21-24) whereas others reported shorter time to resolution of disease manifestations that were attributed to COVID-19,(25-27) greater reduction in inflammatory marker levels,(26) shorter time to viral clearance,21 or lower mortality rates in patients who received ivermectin than in patients who received comparator drugs or placebo.(21,27) However, most of these studies had incomplete information and significant methodological limitations, which make it difficult to exclude common causes of bias.


These limitations include:

  • The sample size of most of the trials was small.

  • Various doses and schedules of ivermectin were used.

  • Some of the randomized controlled trials were open-label studies in which neither the participants nor the investigators were blinded to the treatment arms.

  • Patients received various concomitant medications (e.g., doxycycline, hydroxychloroquine, azithromycin, zinc, corticosteroids) in addition to ivermectin or the comparator drug. This confounded the assessment of the efficacy or safety of ivermectin.

  • The severity of COVID-19 in the study participants was not always well described.

  • The study outcome measures were not always clearly defined.

Table 2c includes summaries of key studies. Because most of these studies have significant limitations, the Panel cannot draw definitive conclusions on the clinical efficacy of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide further guidance on the role of ivermectin in the treatment of COVID-19. Monitoring, Adverse Effects, and Drug-Drug Interactions

  • Ivermectin is generally well tolerated. Adverse effects may include dizziness, pruritis, nausea, or diarrhea.

  • Neurological adverse effects have been reported with the use of ivermectin for the treatment of onchocerciasis and other parasitic diseases, but it is not clear whether these adverse effects were caused by ivermectin or the underlying conditions.28

  • Ivermectin is a minor cytochrome P 3A4 substrate and a p-glycoprotein substrate.

  • Ivermectin is generally given on an empty stomach with water; however, administering ivermectin with food increases its bioavailability.

  • The FDA issued a warning in April 2020 that ivermectin intended for use in animals should not be used to treat COVID-19 in humans.

  • Please see Table 2c for additional information.

Considerations in Pregnancy

In animal studies, ivermectin was shown to be teratogenic when given in doses that were maternotoxic. These results raise concerns about administering ivermectin to people who are in the early stages of pregnancy (prior to 10 weeks gestation).(29) A 2020 systematic review and meta-analysis reviewed the incidence of poor maternal and fetal outcomes after ivermectin was used for its antiparasitic properties during pregnancy. However, the study was unable to establish a causal relationship between ivermectin use and poor maternal or fetal outcomes due to the quality of evidence. There are numerous reports of inadvertent ivermectin use in early pregnancy without apparent adverse effects.(30-32) Therefore, there is insufficient evidence to establish the safety of using ivermectin in pregnant people, especially those in the later stages of pregnancy. One study reported that the ivermectin concentrations secreted in breastmilk after a single oral dose were relatively low. No studies have evaluated the ivermectin concentrations in breastmilk in patients who received multiple doses.

Considerations in Children Ivermectin is used in children weighing >15 kg for the treatment of helminthic infections, pediculosis, and scabies. The safety of using ivermectin in children weighing <15 kg has not been well established. Ivermectin is generally well tolerated in children, with a side effect profile similar to the one seen in adults. Currently, there are no available pediatric data from clinical trials to inform the use of ivermectin for the treatment or prevention of COVID-19 in children.

Clinical Trials Several clinical trials that are evaluating the use of ivermectin for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.


References

  1. Spoorthi V, Sasank S. Utility of ivermectin and doxycycline combination for the treatment of SARS-CoV-2. Int Arch Integr Med. 2020;7(10):117-182. Available at: https://iaimjournal.com/wp-content/uploads/2020/10/iaim_2020_0710_23.pdf.

  2. Camprubi D, Almuedo-Riera A, Marti-Soler H, et al. Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients. PLoS One. 2020;15(11):e0242184. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33175880.

  3. Bhattacharya R, Ray I, Mukherjee R, Chowdhury S, Kulasreshtha MK, Ghosh R. Observational study on clinical features, treatment and outcome of COVID-19 in a tertiary care centre in India - a retrospective case series. Int J Sci Res. 2020;9(10). Available at: https://www.worldwidejournals.com/international-journal-of-scientific-research-(IJSR)/article/observational-study-on-clinical-features-treatment-and-outcome-of-covid-19-in-a-tertiary-care-centre-in-india-andndash-a-retrospective-case-series/MzI0NTg=/?is=1&b1=141&k=36.

  4. Morgenstern J, Redondo JN, León A, et al. The use of compassionate ivermectin in the management of symptomatic outpatients and hospitalized patients with clinical diagnosis of COVID-19 at the Medical Center Bournigal and the Medical Center Punta Cana, Rescue Group, Dominican Republic, from May 1 to August 10, 2020. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.29.20222505v1.

  5. Cadegiani FA, Goren A, Wambier CG, McCoy J. Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly reduced symptoms compared to known outcomes in untreated patients. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.31.20223883v1.

  6. Carvallo H, Roberto H, Eugenia FM. Safety and efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against COVID 19. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.09.10.20191619v1.

  7. Bukhari KHS, Asghar A, Perveen N, et al. Efficacy of ivermectin in COVID-19 patients with mild to moderate disease. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.02.21250840v1.

  8. Elalfy H, Besheer T, El-Mesery A, et al. Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19. J Med Virol. 2021;93(5):3176-3183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33590901.

  9. Chahla RE, Ruiz LM, Mena T, et al. Cluster randomised trials—ivermectin repurposing for COVID-19 treatment of outpatients with mild disease in primary health care centers. Research Square. 2021;Preprint. Available at: https://www.researchsquare.com/article/rs-495945/v1.

  10. Tanioka H, Tanioka S, Kaga K. Why COVID-19 is not so spread in Africa: how does ivermectin affect it? medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.26.21254377v1.

  11. Roy S, Samajdar SS, Tripathi SK, Mukherjee S, Bhattacharjee K. Outcome of different therapeutic interventions in mild COVID-19 patients in a single OPD clinic of West Bengal: a retrospective study. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.08.21252883v2.

  12. Pott-Junior H, Bastos Paoliello MM, Miguel AQC, et al. Use of ivermectin in the treatment of COVID-19: a pilot trial. Toxicol Rep. 2021;8:505-510. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33723507.

  13. Merino J, Borja VH, Lopez O, et al. Ivermectin and the odds of hospitalization due to COVID-19: evidence from a quasi-experimental analysis based on a public intervention in Mexico City. SocArXiv Papers. 2021;Preprint. Available at: https://osf.io/preprints/socarxiv/r93g4/.

  14. Shahbaznejad L, Davoudi A, Eslami G, et al. Effects of ivermectin in patients with COVID-19: a multicenter, double-blind, randomized, controlled clinical yrial. Clin Ther. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34052007.

  15. Samaha AA, Mouawia H, Fawaz M, et al. Effects of a single dose of ivermectin on viral and clinical outcomes in asymptomatic SARS-CoV-2 infected subjects: a pilot clinical trial in Lebanon. Viruses. 2021;13(6). Available at: https://www.ncbi.nlm.nih.gov/pubmed/34073401. This paper was retracted on October 26, 2021.

  16. Roman YM, Burela PA, Pasupuleti V, Piscoya A, Vidal JE, Hernandez AV. Ivermectin for the treatment of COVID-19: a systematic review and meta-analysis of randomized controlled trials. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.05.21.21257595v2.full.

  17. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426-1435. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33662102.

  18. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2020;103:214-216. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33278625.

  19. Okumus N, Demirturk N, Cetinkaya RA, et al. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. BMC Infect Dis. 2021;21(1):411. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33947344.

  20. Galan LEB, Santos NMD, Asato MS, 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. 2021;115(4):235-242. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33682640.

  21. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of ivermectin in SARS-COV-2/COVID-19 Patients. Int J of Sci. 2020;9:31-35. Available at: https://www.ijsciences.com/pub/article/2378.

  22. Podder CS, Chowdhury N, Sina MI, Haque W. Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC J of Med Sci. 2020. Available at: https://doi.org/10.3329/imcjms.v14i2.52826.

  23. Chowdhury ATMM, Shahbaz M, Karim MR, Islam J, Dan G, He S. A comparative study on ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on COVID-19 patients. EJMO. 2021;5(1):63-70. Available at: https://ejmo.org/pdf/A%20Comparative%20Study%20on%20IvermectinDoxycycline%20and%20HydroxychloroquineAzithromycin%20Therapy%20on%20COVID19%20Patients-16263.pdf.

  24. Krolewiecki A, Lifschitz A, Moragas M, et al. Antiviral effect of high-dose ivermectin in adults with COVID-19: a proof-of-concept randomized trial. Lancet. 2021. Available at: https://www.sciencedirect.com/science/article/pii/S258953702100239X?via%3Dihub.

  25. Chaccour C, Casellas A, Blanco-Di Matteo A, 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. Lancet. 2021. Available at: https://www.thelancet.com/action/showPdf?pii=S2589-5370%2820%2930464-8.

  26. Hashim HA, Maulood MF, Rasheed AW, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1/.

  27. Mohan A, Tiwari P, Suri T, et al. Ivermectin in mild and moderate COVID-19 (RIVET-COV): a randomized, placebo-controlled trial. Research Square. 2021;Preprint. Available at: https://www.researchsquare.com/article/rs-191648/v1.

  28. Gonzalez JLB, Gámez MG, Enciso EAM, et al. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.18.21252037v1.

  29. Niaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-109670/v1.

  30. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ICON study. Chest. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33065103.

  31. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.

  32. Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with COVID-19. Arch Bronconeumol. 2020;56(12):828-830. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293006.


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