Fluvoxamine for the treatment of COVID-19
Authors: David R Boulware, Mahsa Abassi
Journal: The Lancet Global Health (2022)

We congratulate Gilmar Reis and colleagues (January, 2022)1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar on their randomised, platform clinical trial (TOGETHER trial) investigating the effects of early treatment with fluvoxamine for patients with COVID-19. In the study, the impressive 5% absolute risk reduction in hospitalisation or prolonged emergency setting observation equates to a number needed to treat of 20, meaning for every 20 individuals treated, one will have this benefit from the treatment.1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar At a US wholesale pharmacy cost of US$4·66, which equates to $93 (95%CI 56–285) to prevent one emergency setting visit or hospitalisation among all participants. The overall objective of early therapy is to prevent clinical deterioration or reduce symptom severity or duration. In this respect, fluvoxamine seems an effective low-cost therapy that provides substantial benefit, particularly in low-income and middle-income countries worldwide where vaccine roll-out and other therapeutics are unavailable. Yet, the authors should explain more regarding the COVID-19 severity and activities occurring during prolonged emergency setting observation. When the authors did their study,1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar it was likely that the COVID-19 acuity was quite high, and in a fully resourced health-care system absent a pandemic, such individuals would have likely been hospitalised. To enable external comparison, the authors should also present the primary endpoint data per the US Food and Drug Administration categorisation of severe COVID-19, which is defined as hospitalisation or emergency setting observation with SpO2 less than 93% or PaO2/FiO2 ratio less than 300.2Food and Drug AdministrationCOVID-19: developing drugs and biological products for treatment or prevention guidance for industry.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/covid-19-developing-drugs-and-biological-products-treatment-or-preventionDate: 2021Date accessed: November 1, 2021Google Scholar The authors should state what proportion of participants in the fluvoxamine and placebo groups progressed to severe COVID-19 and whether fluvoxamine prevented progression to severe COVID-19. Yet, one question remains as to what is the optimal fluvoxamine dose. This trial result builds off a smaller randomised controlled trial and prospective cohort.3Lenze EJ Mattar C Zorumski CF et al.Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial.JAMA. 2020; 324: 2292-2300Crossref PubMed Scopus (211) Google Scholar, 4Seftel D Boulware DR Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19.Open Forum Infect Dis. 2021; 8ofab050Crossref PubMed Scopus (55) Google Scholar In the per-protocol analysis of those more than 80% adherent to fluvoxamine or placebo before any clinical deterioration, emergency room visits or hospitalisations were reduced by two-thirds and mortality by 91% (one vs 12 deaths).1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar Lenze and colleagues used 300 mg per day,3Lenze EJ Mattar C Zorumski CF et al.Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial.JAMA. 2020; 324: 2292-2300Crossref PubMed Scopus (211) Google Scholar Reis and colleagues used 200 mg per day,1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar and Seftel and colleagues used 100 mg per day,4Seftel D Boulware DR Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19.Open Forum Infect Dis. 2021; 8ofab050Crossref PubMed Scopus (55) Google Scholar all in twice per day divided dosing; however, what dose schedule is optimal for effect and tolerability is unclear. University of Minnesota (CovidOut.com; NCT04510194) and NIH ACTIV-6 trials (NCT04885530) are testing 50 mg twice daily. This lower dose will probably be more tolerable, but whether the clinical benefit will be similar is unknown yet. Lastly, strategies of supportive care should be investigated. In the TOGETHER trial, individuals who were not adherent to fluvoxamine or placebo1Reis G Dos Santos Moreira-Silva EA Silva DCM et al.Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.Lancet Glob Health. 2022; 10: e42-e51Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar had an eight-times higher mortality than did those adherent to fluvoxamine or placebo (29 of [9%] of 331) vs 13 [1%] of 1166; p<0·001). Ill COVID-19 patients who cannot tolerate any oral medicine appear to be at substantially higher risk for clinical deterioration. Earlier provision of anti-nausea or anti-motility medication (eg, ondansetron or loperamide) should be investigated both as supportive care to improve the tolerability of fluvoxamine and perhaps for patients with COVID-19 in general.5Dong ZY Xiang BJ Jiang M Sun MJ Dai C The prevalence of gastrointestinal symptoms, abnormal liver function, digestive system disease and liver disease in COVID-19 Infection: A systematic review and meta-analysis.J Clin Gastroenterol. 2021; 55: 67-76Crossref PubMed Scopus (23) Google Scholar We declare no competing interests. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trialTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19In the TOGETHER study,1 Gilmar Reis and colleagues showed a benefit of early treatment with fluvoxamine with notably a reduction in the need for hospitalisation, which was defined as retention in a COVID-19 emergency setting for more than 6 h or transfer to a tertiary hospital.1 The authors mentioned that the findings of their study, together with fluvoxamine's safety, tolerability, ease of use, low cost, and widespread availability, might influence national and international guidelines on the clinical management of COVID-19. Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19The clinical efficacy of fluvoxamine observed in the TOGETHER trial1 (although no change in virological outcomes was observed) might be related to anti-inflammatory effects via sigma-1 receptor agonism,2 but several other possible mechanisms warrant further investigation.3 Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19 – Author's replyWe are grateful for the communications pertaining to our trial.1 After publication, we noticed that some decision-making groups might not have the correct understanding of composite endpoints. Composite endpoint guidance is well-established. Strictly speaking, all clinical endpoints are a form of composite (eg, death can be from different reasons).2 If we apply the same composite endpoint (hospitalisation or emergency care >24 h) used in the paxlovid trial3 and molnupiravir trial,4 our effect size does not change importantly (relative risk [RR] 0·74 [95% CI 0·56–0·98]). Full-Text PDF Open AccessFluvoxamine for the treatment of COVID-19We read with interest the investigation by Gilmar Reis and colleagues1 who studied the repurposing of fluvoxamine for the mitigation of hospitalisation risk among acutely symptomatic patients with COVID-19 in Brazil. Although impressive, their observation that a 10-day course of fluvoxamine resulted in an absolute risk reduction of 5% and a relative risk reduction of 32% for hospitalisations might be an underestimate of its potential efficacy. Full-Text PDF Open Access