Recommendation for use of Ivermectin in the Treatment of COVID-19

Ivermectin is an antiparasitic drug that is approved by the Food and Drug Administration (FDA) for the treatment of onchocerciasis and strongyloidiasis. Ivermectin is not FDA-approved for the treatment of any viral infection. In general, the drug is well tolerated. It is currently being evaluated as a potential treatment for COVID-19.

Ivermectin is a drug initially synthesized and used as an anthelmintic. It has been found to have activity against several RNA viruses such as the SARS-CoV-2 by mechanisms that inhibit importin α/β-mediated nuclear transport that may prevent viral proteins from entering the nucleus to alter host cell function. A recent in vitro study showed that a single dose of ivermectin could kill COVID-19 in vitro within 48 hours.

A recent multi-continent retrospective study of 1,400 patients demonstrated an association of ivermectin use with lower in-hospital mortality 1.4% versus 8.5%. Given these findings and its safety profile, cost and ease of administration, Ivermectin warrants study as a potential treatment to prevent progression of COVID 19 infection.

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Antiviral and Anti-Inflammatory Effects of Ivermectin

Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alfa/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host antiviral response.^1,2 In addition, ivermectin docking in vitro may interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to the human cell membrane.

Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in cell culture. However, pharmacokinetic and pharmacodynamic studies suggest that ivermectin doses up to 100-fold higher than those approved for use in humans would be required to achieve the plasma concentrations necessary to duplicate the drug’s antiviral efficacy in vitro. Even though ivermectin appears to accumulate in lung tissue, with the doses used in most clinical trials, 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.

Ivermectin demonstrates potential anti-inflammatory properties in some in vitro studies, properties which have been postulated to be beneficial in the treatment of COVID-19.

Is there an EUA for ivermectin in the U.S. to prevent or treat COVID-19?

No. While there are approved uses for ivermectin in people and animals, it is not approved for the prevention or treatment of COVID-19. You should not take any medicine to treat or prevent COVID-19 unless it has been prescribed to you by your health care provider and acquired from a legitimate source.

A recently released described the effect of ivermectin on SARS-CoV-2 in a laboratory setting. These types of laboratory studies are commonly used at an early stage of drug development. Additional testing is needed to determine whether ivermectin might be appropriate to prevent or treat coronavirus or COVID-19.

Incomplete clinical data

However, most of the studies reported to date had incomplete information and significant methodological limitations, which make it difficult to exclude common causes of bias. The missing information and limitations include the following:

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.
In addition to ivermectin or the comparator drug, patients also received various concomitant medications (e.g., doxycycline, hydroxychloroquine, azithromycin, zinc, corticosteroids), confounding assessment of the true 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.

Recommendation

The COVID-19 Treatment Guidelines Panel (the Panel) has determined that currently there are insufficient data 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 for the treatment of COVID-19.

Conclusion

Because of these limitations, the Panel cannot draw definitive conclusions about the clinical efficacy or safety 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 for the treatment of COVID-19.

More research is needed to determine if an antiviral effect would be elicited in humans, as the concentrations tested were much higher than what is achieved from the normal oral dose.

Available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans.

Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans.