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. 2022 Sep 14;9(9):CD015391.
doi: 10.1002/14651858.CD015391.

Fluvoxamine for the treatment of COVID-19

John Lz Nyirenda  1   2 , Mario Sofroniou  3   4   5 , Ingrid Toews  1 , Agata Mikolajewska  6   7 , Cornelius Lehane  8 , Ina Monsef  9 , Aesha Abu-Taha  3 , Andy Maun  3 , Miriam Stegemann  7 , Christine Schmucker  1
Affiliations

Fluvoxamine for the treatment of COVID-19

John Lz Nyirenda et al. Cochrane Database Syst Rev. .

Abstract

Background: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been approved for the treatment of depression, obsessive-compulsive disorder, and a variety of anxiety disorders; it is available as an oral preparation. Fluvoxamine has not been approved for the treatment of infections, but has been used in the early treatment of people with mild to moderate COVID-19. As there are only a few effective therapies for people with COVID-19 in the community, a thorough understanding of the current evidence regarding the efficacy and safety of fluvoxamine as an anti-inflammatory and possible anti-viral treatment for COVID-19, based on randomised controlled trials (RCTs), is needed.

Objectives: To assess the efficacy and safety of fluvoxamine in addition to standard care, compared to standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy for the treatment of COVID-19 outpatients and inpatients.

Search methods: We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv), Web of Science and WHO COVID-19 Global literature on COVID-19 to identify completed and ongoing studies up to 1 February 2022.

Selection criteria: We included RCTs that compared fluvoxamine in addition to standard care (also including no intervention), with standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy in clinical trials for the treatment of people with confirmed COVID-19, irrespective of disease severity, in both inpatients and outpatients. Co-interventions needed to be the same in both study arms. We excluded studies comparing fluvoxamine to other pharmacological interventions with unproven efficacy.

Data collection and analysis: We assessed risk of bias of primary outcomes using the Cochrane Risk of Bias 2 tool for RCTs. We used GRADE to rate the certainty of evidence to treat people with asymptomatic to severe COVID-19 for the primary outcomes including mortality, clinical deterioration, clinical improvement, quality of life, serious adverse events, adverse events of any grade, and suicide or suicide attempt.

Main results: We identified two completed studies with a total of 1649 symptomatic participants. One study was conducted in the USA (study with 152 participants, 80 and 72 participants per study arm) and the other study in Brazil (study with 1497 high-risk participants for progression to severe disease, 741 and 756 participants per study arm) among outpatients with mild COVID-19. Both studies were double-blind, placebo-controlled trials in which participants were prescribed 100 mg fluvoxamine two or three times daily for a maximum of 15 days. We identified five ongoing studies and two studies awaiting classification (due to translation issues, and due to missing published data). We found no published studies comparing fluvoxamine to other pharmacological interventions of proven efficacy. We assessed both included studies to have an overall high risk of bias. Fluvoxamine for the treatment of COVID-19 in inpatients We did not identify any completed studies of inpatients. Fluvoxamine for the treatment of COVID-19 in outpatients Fluvoxamine in addition to standard care may slightly reduce all-cause mortality at day 28 (RR 0.69, 95% CI 0.38 to 1.27; risk difference (RD) 9 per 1000; 2 studies, 1649 participants; low-certainty evidence), and may reduce clinical deterioration defined as all-cause hospital admission or death before hospital admission (RR 0.55, 95% CI 0.16 to 1.89; RD 57 per 1000; 2 studies, 1649 participants; low-certainty evidence). We are very uncertain regarding the effect of fluvoxamine on serious adverse events (RR 0.56, 95% CI 0.15 to 2.03; RD 54 per 1000; 2 studies, 1649 participants; very low-certainty evidence) or adverse events of any grade (RR 1.06, 95% CI 0.82 to 1.37; RD 7 per 1000; 2 studies, 1649 participants; very low-certainty evidence). Neither of the studies reported on symptom resolution (clinical improvement), quality of life or suicide/suicide attempt.

Authors' conclusions: Based on a low-certainty evidence, fluvoxamine may slightly reduce all-cause mortality at day 28, and may reduce the risk of admission to hospital or death in outpatients with mild COVID-19. However, we are very uncertain regarding the effect of fluvoxamine on serious adverse events, or any adverse events. In accordance with the living approach of this review, we will continually update our search and include eligible trials as they arise, to complete any gaps in the evidence.

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Conflict of interest statement

John Nyirenda (JN): has no known conflicts of interest to declare.

Mario Sofroniou (MSo): has no known conflicts of interest to declare.

Ingrid Toews (IT): has no known conflicts of interest to declare.

Agata Mikolajewska (AMi): is affiliated with not‐for‐profit organisation: Coordination of Section COVRIIN and Work in Office of STAKOB (Competence and Treatment Centres for high consequence infectious diseases) at Robert Koch Institute Centre for Biological Threats and Special Pathogens (ZBS), Section Clinical Management and Infection Control.

Cornelius Lehane (CL): has no known conflicts of interest to declare.

Ina Monsef (IM): has no known conflicts of interest to declare. She is part of the Cochrane Haematology editorial team, but was not involved in the editorial process of this review.

Aesha Abu‐taha (AA): has no known conflicts of interest to declare.

Andy Maun (AMa) is a member of the guideline group 'Covid 19, Ambulatory Treatment', member of the German College of General Practitioners and Family Physicians, and affiliated with the Practice Kreusel/Höltner, Titisee‐Neustadt, Germany (employed as a General Practitioner).

Miriam Stegemann (MSt): has no known conflicts of interest to declare.

Christine Schmucker (CS): has no known conflicts of interest to declare.

Figures

1
1
Figure 1: PRISMA flow diagram of study selection
1.1
1.1. Analysis
Comparison 1: Fluvoxamine plus standard care compared to placebo plus standard care for outpatients with mild COVID‐19, Outcome 1: All‐cause mortality (at day 28)
1.2
1.2. Analysis
Comparison 1: Fluvoxamine plus standard care compared to placebo plus standard care for outpatients with mild COVID‐19, Outcome 2: All‐cause hospital admission or death (before hospital admission)
1.3
1.3. Analysis
Comparison 1: Fluvoxamine plus standard care compared to placebo plus standard care for outpatients with mild COVID‐19, Outcome 3: Serious adverse events
1.4
1.4. Analysis
Comparison 1: Fluvoxamine plus standard care compared to placebo plus standard care for outpatients with mild COVID‐19, Outcome 4: Adverse events (any grade)
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