Fluvoxamine for the treatment of COVID-19
Authors: Catia Marzolini, Fiona Marra, Alison Boyle, Saye Khoo, David J Back
Journal: The Lancet Global Health (2022)

In the TOGETHER 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 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.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 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. We wish to comment further to raise awareness of the fact that fluvoxamine has a high potential for drug–drug interactions (appendix),2University of LiverpoolCOVID-19 Drug interaction.https://www.covid19-druginteractions.orgDate accessed: November 23, 2021Google Scholar which needs to be considered when prescribing in patients with COVID-19. On the one hand, the antidepressant fluvoxamine is mainly metabolised by the cytochrome P450 (CYP) enzyme CYP2D6 and therefore can be effected by comedications inhibiting this enzyme. On the other hand, fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19, as well as a moderate inhibitor of CYP2C9, CYP2D6, and CYP3A4 and consequently can increase the exposure of comedications metabolised by these enzymes.3Van Harten J Overview of the pharmacokinetics of fluvoxamine.Clin Pharmacokinet. 1995; 29: 1-9Crossref PubMed Scopus (92) Google Scholar, 4Jazz PharmaceuticalsFluvoxamine (Luvox highlights of prescribing information 2008).https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022235lbl.pdfDate: Nov 23, 2021Google Scholar CYP inhibition is expected to occur immediately after initiation of fluvoxamine. Therefore, although the time course of fluvoxamine treatment is relatively short (10 days),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 drug–drug interactions cannot be ignored and their management can be challenging particularly for comedications whose dosage is titrated based on the clinical response (eg, antiepileptics, antidepressants, and neuroleptics). Their dosage would have to be reduced and increased again within a 2-week period, which can potentially destabilise the patient. Other concerns relate to the potential of fluvoxamine to cause serotonin toxicity or to prolong the QT interval when combined with comedications carrying this same risk. Caution is also warranted when prescribing fluvoxamine to patients with diabetes as glycaemic control might be altered; therefore, potentially requiring a dosage adjustment of the antidiabetic drug. Finally, coadministration of fluvoxamine is contraindicated with drugs that inhibit monoamine oxidase (eg, linezolid, phenelzine, and tranylcypromine) because such combinations might raise serotonin levels and consequently lead to elevated blood pressure, tremor, confusion, coma, and death. Patients with COVID-19 are often at high risk of drug–drug interactions due to the presence of comorbidities and related polypharmacy. Therefore, we wish to highlight that consideration should be given to stop non-essential medications to limit drug–drug interactions. The benefit of starting a treatment with fluvoxamine should be balanced against the risk of a potential drug–drug interactions, and drug–drug interactions should be systematically screened using specialised, up-to-date web resources.2University of LiverpoolCOVID-19 Drug interaction.https://www.covid19-druginteractions.orgDate accessed: November 23, 2021Google Scholar CM received a research grant from Gilead; and lecture honoraria from Merck Sharpe and Dohme and ViiV Healthcare. FM has received an educational grant from Gilead Sciences and Abbvie; consultancy fees from Gilead Sciences, ViiV Healthcare, and Merck; and lecture fees from Gilead and ViiV. AB has received educational grants and lecture honoraria from Gilead and Abbvie. SK has received educational grants for the Liverpool drug interaction website (www.covid-druginteractions.org), AbbVie, Gilead Sciences, Merck Sharpe and Dohme, Novartis, and Sobi; speakers' honoraria from ViiV Healthcare, Gilead Sciences, and AbbVie; consultancy fees from ViiV Healthcare and Merck; and research funding from Gilead Sciences, and ViiV Healthcare. DJB has received educational grants from AbbVie, Novartis, Merck, Gilead, and Sobi; DJB has received lecture fees from AbbVie, Gilead Sciences, Merck, ViiV Healthcare; and consultancy fees from Gilead Sciences. Download .pdf (.14 MB) Help with pdf files Supplementary appendix 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-19We congratulate Gilmar Reis and colleagues (January, 2022)1 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.1 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. 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