H2 Blockers in COVID-19

Clinical Question

Cimetidine/Famotidine and other H2 Blockers as COVID-19 Treatment

Key Findings

  • Famotidine has shown an inhibitory effect of HIV replication in vitro, and it has been identified as an inhibitory agent 3-chymotrypsin-like protease (3CLpro), a proteolytic enzyme essential for SARS-CoV-2 replication;
  • We could only find one study of the use of famotidine in COVID-19 patients. Famotidine was associated with reduced risk of death and intubation independent of age, BMI, and comorbidities. The hazard ratio of famotidine and death or intubation was 0.42, 95% CI 0.21-0.85, and the hazard ratio of famotidine and death was 0.30, 95% CI 0.11-0.80;
  • However, this study was not a randomized controlled trial and did not establish the preferred route of administration or dose of famotidine to be used in COVID-19 cases.
  • While the results of the one study are encouraging, at this time, there is insufficient data whether famotidine can be recommended as a treatment for COVID-19.
  • There are currently no known published studies examining the role of cimetidine in COVID-19.

Summary of Information

Evidence has indicated that high rates of viral replication in the initial stage of COVID-19 can result in a massive cytokine release syndrome and clinical deterioration.[1] Famotidine, a histamine H2 receptor antagonist, has shown to inhibit HIV replication in vitro.[2] The SARS-CoV-2 viral replication requires a key proteolytic enzyme 3-chymotrypsin-like-protease (3CLpro).[3] A recent model identified famotidine as a pharmaceutical agent that can inhibit 3CLpro.[4] This finding has led to the hypothesis that famotidine could be associated with a reduced incidence of cytokine release syndrome and clinical deterioration in patients with COVID-19.

Famotidine Review

A literature review using PubMed to collect articles with keywords coronavirus, 2019-nCoV, SARS-CoV-2, SARS-CoV, COVID-19, famotidine yielded no result. The only relevant literature that we were able to find is a clinical study done in New York Hospitals.[5] This study involved 1,620 patients, and 5.1% of these patients (n = 84) received famotidine within 24 hours of admission. The primary endpoint of this study was death or intubation. After adjusting for baseline patient characteristics, the results showed that famotidine was associated with risk of death or intubation with an adjusted hazard ratio of 0.42, 95% CI 0.21-0.85. When the outcome was set to death only, famotidine remained associated with the risk for death with an adjusted hazard ratio of 0.30, 95% CI 0.11-0.80. The study concluded that famotidine use was associated with a significant reduction in the risk of clinical deterioration that required intubation or death. Additionally, the result was only observed in COVID-19 patients and only in famotidine and not proton pump inhibitors. As omeprazole can suppress gastric acid, this finding ruled pH changes as a potential explanation for famotidine and its reduced risk for deaths and intubation. Although the study results were statistically significant, this study was neither based on multiple medical centers nor randomized control. Without robust evidence and better design studies, further data are needed to determine whether famotidine should be recommended in clinical practice.

Cimetidine Review

Although cimetidine is also a histamine H2 receptor, the computational model mentioned previously did not yield cimetidine as a potential 3CLpro inhibitor.[4] The only relevant studies of cimetidine and the immune system was a study in 2019 that reviewed cimetidine and its effect in reducing suppressor T-cell and potentiating immunologic activity in vitro and in vivo.[6] There are currently no published studies examining the role of cimetidine in COVID-19.

Gaps in knowledge:

The ideal dose and route of administration of famotidine to be effective is not yet known. In Freedberg’s study, there was a variety of dosing given orally or intravenously to patients. Further research is needed to investigate the most optimal dose and route.
Proton pump inhibitors were not shown to be associated with risk for deaths and intubation in this study, but other data suggest that omeprazole could increase the efficacy of acyclovir during HSV viral replication and might increase the activity of remedesivir against COVID-19.[7][8] It might be of interest to conduct studies on the effect of omeprazole in the early stage of SARS-CoV-2 and among patients receiving remedesivir for COVID-19.

Author Information

Authors: Jon Zhou, Pharm.D., MPH
Completed on: May 12, 2020
Last revised on: Not yet revised

Reviewed by: Gary Smithson
Reviewed on: May 19, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu

References

  1. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473-474.  [PMID:32303591]
  2. Bourinbaiar AS, Fruhstorfer EC. The effect of histamine type 2 receptor antagonists on human immunodeficiency virus (HIV) replication: identification of a new class of antiviral agents. Life Sci. 1996;59(23):PL 365-70.  [PMID:8950301]
  3. Anand K, Ziebuhr J, Wadhwani P, et al. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science. 2003;300(5626):1763-7.  [PMID:12746549]
  4. Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020.  [PMID:32292689]
  5. Freedberg DE, Conigliaro J, Wang TC, et al. Famotidine Use is Associated with Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study. Gastroenterology. 2020.  [PMID:32446698]
  6. Jafarzadeh A, Nemati M, Khorramdelazad H, et al. Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases. Int Immunopharmacol. 2019;70:156-166.  [PMID:30802678]
  7. Michaelis M, Kleinschmidt MC, Bojkova D, et al. Omeprazole Increases the Efficacy of Acyclovir Against Herpes Simplex Virus Type 1 and 2. Front Microbiol. 2019;10:2790.  [PMID:31849920]
  8. Bojkova D, McGreig JE, McLaughlin K-M, et al. SARS-CoV-2 and SARS-CoV differ in their cell tropism and drug sensitivity profiles. bioRxiv. Published online April 5, 2020:2020.04.03.024257. doi:10.1101/2020.04.03.024257