Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
  • Users Online: 381
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
SYSTEMATIC REVIEW
Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 47-53

Mucocutaneous adverse effects of remdesivir and favipiravir in patients with Covid-19 infection: A systematic review


Department of Dermatology, Zoram Medical College, Mizoram, India

Date of Submission17-Sep-2021
Date of Decision08-May-2022
Date of Acceptance18-May-2022
Date of Web Publication27-Oct-2022

Correspondence Address:
Pradeep Balasubramanian
Department of Dermatology, Zoram Medical College, Mizoram
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdpdd.ijdpdd_70_21

Rights and Permissions
  Abstract 

Introduction: Remdesivir and favipiravir are two antiviral medicines used in the treatment of Covid-19 infection widely. The studies pertaining to the mucocutaneous adverse events of these two drugs are scarce. Hence, we performed a systematic review to bridge the above gap. Materials and Methods: The study is performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. All original articles, case series, and case reports pertaining to mucocutaneous adverse drug reactions caused by remdesivir and favipiravir, while any of these drugs were administered in Covid-19-infected patients, were included in the present study. Results: Six articles were identified pertaining to the mucocutaneous adverse reactions of remdesivir, of which two were original articles and four were case reports. Four case reports pertaining to the mucocutaneous adverse events of favipiravir are included in this study. The details regarding the same are elaborated in the main manuscript. Conclusion: In the present systematic analysis, the mucocutaneous adverse events of the two widely used antiviral medications in Covid-19 were described. This articles throws light on the aspects which are hardly reported or discussed in the literature.

Keywords: Favipiravir, mucocutaneous adverse effects, remdesivir


How to cite this article:
Balasubramanian P, Laldinthari C, Lalnunpuia R. Mucocutaneous adverse effects of remdesivir and favipiravir in patients with Covid-19 infection: A systematic review. Indian J Dermatopathol Diagn Dermatol 2022;9:47-53

How to cite this URL:
Balasubramanian P, Laldinthari C, Lalnunpuia R. Mucocutaneous adverse effects of remdesivir and favipiravir in patients with Covid-19 infection: A systematic review. Indian J Dermatopathol Diagn Dermatol [serial online] 2022 [cited 2022 Nov 26];9:47-53. Available from: https://www.ijdpdd.com/text.asp?2022/9/2/47/359774




  Introduction Top


Remdesivir (formerly GS-5734) is a broad-spectrum antiviral medication. It was first developed by Gilead Sciences for the treatment of Ebola virus infection in West Africa (2014–2016).[1],[2] It has been reported to exert activity in animal models and cell culture against SARS-CoV, MERS-CoV, and SARS-CoV-2.[3] It is a prodrug, a nucleoside analog, which on entering into the human respiratory epithelial cells gets metabolized to a nucleoside triphosphate which is the active form. It inhibits the viral RNA-dependent RNA polymerase (RdRp) by competing with the usual counterpart adenosine triphosphate. The nucleoside analog is incorporated into the generating RNA strands of the virus and causes a delayed stop in the viral replication process.[4]

On May 1, 2020, the U.S. Food and Drug Administration (FDA) has granted Emergency Use Authorization (EUA) for remdesivir to treat Covid-19 patients.[5] For adults and children weighing ≥ 40 kg requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), the recommended dose is 200 mg IV on day 1 followed by 100 mg IV once daily on days 2–10.[6],[7] For those not requiring invasive mechanical ventilation or ECMO, a 5-day regimen is recommended. Doses should be administered over 30 min to 2 h.

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazine​carboxamide) is a purine nucleoside analog. It has a broad-spectrum antiviral activity and it is demonstrated to inhibit, in vitro and in animal models, the replication of different RNA viruses, including flaviviruses,[8] norovirus,[9] and hantaviruses.[10] It was first permitted for use in Japan for the treatment of influenza in 2014. It was further studied for use against Ebola[11] and now SARS-CoV-2 in China in 2019. In June 2020, favipiravir received the Drug Controller General of India approval in India for mild and moderate Covid-19 infections.[12]

Favipiravir acts by competitive inhibition of viral RdRp. Within the tissue, the molecule undergoes phosphoribosylation to its active form favipiravir-favipiravir ribofuranosyl-5′-triphosphate (RTP). The active favipiravir-RTP inhibits RdRp and prevents replication of the viral genome. Also, it gets incorporated in the viral RNA strand, preventing further elongation and proliferation.[13] The recommended dosage of favipiravir for adults is 1800 mg orally twice daily on 1st day followed by 800 mg orally twice daily, up to a maximum of 14 days.[14]

In the present article, a systematic review of mucocutaneous adverse effects of remdesivir and favipiravir which are the two antiviral drugs used widely during the pandemic of Covid-19 was performed.


  Materials and Methods Top


The study is performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The PRISMA flow charts regarding the article search for remdesivir and favipiravir are mentioned as [Figure 1] and [Figure 2].
Figure 1: PRISMA 2020 flow diagram for the present systematic review of remdesivir

Click here to view
Figure 2: PRISMA 2020 flow diagram for the systematic review of favipiravir

Click here to view


Eligibility criteria

All original articles, case series, and case reports pertaining to mucocutaneous adverse drug reactions caused by either remdesivir or favipiravir administered to Covid-19-infected patients were included in the present study. The exclusion criteria comprised animal studies, in-vitro studies, review articles, and all the articles which did not meet the above inclusion criteria.

Source of information

The articles were searched in the following databases: PubMed (http://pubmed.ncbi.nlm.nih.gov) and Google Scholar (https://scholar.google.com).

Search strategy

The search was conducted using the following keywords: (“remdesivir”) AND (“cutaneous adverse drug reaction” OR “mucocutaneous adverse drug reaction” OR “drug reaction” OR “drug rash” OR “skin rash” OR “rash” OR “skin adverse reactions” OR “adverse effects skin” OR “urticarial” OR “maculopapular” OR “erythroderma” OR “steven Johnson syndrome” OR “toxic epidermal necrolysis” OR “erythema multiforme” OR “blister” OR “acute generalised exanthematous pustulosis” OR “drug hypersensitivity syndrome”).

The term “remdesivir” was replaced by “favipiravir” to search the articles regarding the cutaneous adverse drug reactions caused by favipiravir. The search was performed from July 30 until August 15, 2021. The period of search was any article published pertaining to the above search terms until August 15, 2021. The search was done in PubMed and Google Scholar.

Study selection

Initially, the search was conducted using the search terms in the databases. The titles and abstracts of the manuscripts were read. If the articles satisfy the eligibility criteria of the present study, the full text of the articles were read and included. All the available data regarding the mucocutaneous adverse effects of remdesivir or favipiravir mentioned in the eligible manuscripts were extracted and the data were compiled. The PRISMA 2020 flow diagrams pertaining to the systematic review of mucocutaneous adverse effects of remdesivir and favipiravir are mentioned in [Figure 1] and [Figure 2].


  Results Top


Based on the above search criteria, six articles were identified pertaining to the mucocutaneous adverse reactions of remdesivir, of which two were original articles and four were case reports, the details of which are presented in [Table 1] and [Table 2]. In the randomized, double blind, placebo controlled trial performed by Wang et al.,[15] it was observed that 11 (7%) patients developed cutaneous rash in the remdesivir arm and 2 patients (3%) developed cutaneous rash in the control arm. In the single-arm study performed by Grein et al.,[16] it was observed that cutaneous rash was witnessed in four patients (8%) in whom remdesivir was administered.
Table 1: Interventional studies which reported the cutaneous rash caused by remdesivir

Click here to view
Table 2: Case reports of the cutaneous adverse effects implicated to remdesivir

Click here to view


The following were the case reports pertaining to the cutaneous adverse events caused by remdesivir: painful blisters of the left hand following extravasation of remdesivir infusion,[17] maculopapular rash following remdesivir infusion in two patients which resolved following withdrawal of remdesivir,[18] and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) caused by remdesivir which resolved spontaneously following the withdrawal of remdesivir.[19]

One case series and one case report pertaining to the mucocutaneous adverse effects of favipiravir were identified based on the search criteria and are presented in [Table 3]. The case reported by Atak et al.[20] is that of a Covid-19-positive man who developed acute generalized exanthematous pustulosis on the 16th day after starting treatment with favipiravir. Punyaratabandhu and Chirachanakul[21] reported cases of maculopapular rash and Stevens–Johnson syndrome in Covid-19-positive patients. But as these patients received multiple drugs apart from favipiravir, favipiravir cannot be solely implicated as the causative drug.
Table 3: Case reports pertaining to mucocutaneous adverse effects of favipiravir

Click here to view



  Discussion Top


In the studies performed by Wang et al.[15] and Grein et al.,[16] it was observed that rash due to remdesivir was observed in 11 (7%) and 4 (8%) patients, respectively. The type of rash was not mentioned in both the studies mentioned earlier. The cutaneous adverse events published as case reports were painful blisters following extravasation of remdesivir,[17] maculopapular rash in two patients,[18] and SDRIFE.[19]

Charan et al.[22] performed a study to compile the suspected adverse drug reactions due to remdesivir mentioned in the World Health Organization (WHO) database. The authors derived the data from Vigibase, which is a database maintained by the WHO. The adverse drug reactions due to remdesivir notified in Vigibase from January 1, 2015 to July 19, 2020 were included. It was observed that adverse events pertaining to skin and subcutaneous tissue were reported in 36 patients. The description of the cutaneous adverse effects is not mentioned in their study.

Kaur et al.[23] conducted a study to analyze the adverse drug reactions of favipiravir. In this study, 194 adverse drug reactions were seen in 93 patients, of which 20 adverse events were skin-related. The following are the cutaneous adverse events due to favipiravir mentioned in the study: pruritus in five patients, rash in five patients (type of rash is not mentioned), erythema in four patients, maculopapular rash in two patients, hair color change in one patient, nail discoloration in one patient, purpura in one patient, and vasculitis in one patient. In the study conducted by Najar Nobari et al.,[24] it was observed that favipiravir has superior adverse effect profile with no or very few side effects being reported.

Intriguing findings of fluorescence involving the nail plate and hair on performing Wood’s lamp examination in patients who were administered favipiravir were reported by Aslan Kayıran et al.[25] It was proposed by the authors that the fluorescence could be caused by metabolite of favipiravir or due to ingredients such as titanium dioxide or ferric oxide present in the tablet. Similar reports of fluorescence of nail and hair were published by Gülseren and Yalıcı-Armagan[26] and Guder and Ozunal.[27]


  Conclusion Top


In the present systematic analysis, the mucocutaneous adverse events of the two widely used antiviral medications in Covid-19 were described. This article throws light on the aspects which are hardly reported or discussed in the literature.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, Mukadi D, et al; PALM Writing Group; PALM Consortium Study Team. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019;381:2293-303.  Back to cited text no. 1
    
2.
Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, et al. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J Med Chem 2017;60:1648-61.  Back to cited text no. 2
    
3.
Zarenezhad E, Behrouz S, Farjam M, Rad MNS A mini review on discovery and synthesis of remdesivir as an effective and promising drug against COVID-19. Russ J Bioorg Chem 2021;47:609-21.  Back to cited text no. 3
    
4.
Hashemian SM, Farhadi T, Velayati AA A review on remdesivir: A possible promising agent for the treatment of COVID-19. Drug Des Devel Ther 2020;14:3215-22.  Back to cited text no. 4
    
5.
Emergency Use Authorization—US Food and Drug Administration. Available from: https://www.fda.gov/media/137564/download. [Last accessed on August 1, 2021].  Back to cited text no. 5
    
6.
European Medicines Agency. Human Medicines Division. Summary on compassionate use. Remdesivir Gilead. Product No. EMEA/H/K/5622/CU. Available from: https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-remdesivirgilead_en.pdf. [Last accessed on August 1, 2021].  Back to cited text no. 6
    
7.
Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Remdesivir (GS5734™). Available from: https://www.fda.gov/media/137566/download. [Last accessed on August 1, 2021].  Back to cited text no. 7
    
8.
Zmurko J, Marques RE, Schols D, Verbeken E, Kaptein SJ, Neyts J The viral polymerase inhibitor 7-deaza-2’-C-methyladenosine is a potent inhibitor of in vitro zika virus replication and delays disease progression in a robust mouse infection model. Plos Negl Trop Dis 2016;10:e0004695.  Back to cited text no. 8
    
9.
Rocha-Pereira J, Jochmans D, Dallmeier K, Leyssen P, Nascimento MS, Neyts J Favipiravir (T-705) inhibits in vitro norovirus replication. Biochem Biophys Res Commun 2012;424:777-80.  Back to cited text no. 9
    
10.
Safronetz D, Falzarano D, Scott DP, Furuta Y, Feldmann H, Gowen BB Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome. Antimicrob Agents Chemother 2013;57:4673-80.  Back to cited text no. 10
    
11.
Mentré F, Taburet AM, Guedj J, Anglaret X, Keïta S, de Lamballerie X, et al. Dose regimen of favipiravir for Ebola virus disease. Lancet Infect Dis 2015;15:150-1.  Back to cited text no. 11
    
12.
Glenmark Gets DCGI Nod for Favipiravir Use in Covid-19. Hindu Business Line. Available from: https://www.thehindubusinessline.com/companies/glenmark-gets-dcgi-nod-for-favipiravir-use-in-covid-19/article31871629.ece. [Last accessed on August 1, 2021].  Back to cited text no. 12
    
13.
Furuta Y, Komeno T, Nakamura T Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 2017;93:449-63.  Back to cited text no. 13
    
14.
Agrawal U, Raju R, Udwadia ZF Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India 2020;76:370-6.  Back to cited text no. 14
    
15.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-78.  Back to cited text no. 15
    
16.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe covid-19. N Engl J Med 2020;382:2327-36.  Back to cited text no. 16
    
17.
Kumar N, Kumar A, Pradhan S, Kumar A, Singh K Painful blisters of left hand following extravasation of remdesivir infusion in COVID-19. Indian J Crit Care Med 2021;25:240-1.  Back to cited text no. 17
    
18.
Dubert M, Visseaux B, Isernia V, Bouadma L, Deconinck L, Patrier J, et al. Case report study of the first five COVID-19 patients treated with remdesivir in France. Int J Infect Dis 2020;98:290-3.  Back to cited text no. 18
    
19.
Heck J, Stichtenoth DO, Mettin R, Jöckel J, Bickel C, Krichevsky B Remdesivir-induced symmetrical drug-related intertriginous and flexural exanthema (SDRIFE)? A case report with review of the literature. Eur J Clin Pharmacol 2021;77:141-4.  Back to cited text no. 19
    
20.
Atak MF, Farabi B, Akbayrak A, Kalelioğlu MB, Rao BK Acute generalized exanthematous pustulosis following treatment with favipiravir in a patient with COVID-19 without hydroxychloroquine use: Report of the first case. J Cosmet Dermatol 2021;20:2387-9.  Back to cited text no. 20
    
21.
Punyaratabandhu P, Chirachanakul P Cutaneous eruption in COVID-19-infected patients in Thailand: An observational descriptive study. J Dermatol 2021;48:14-20.  Back to cited text no. 21
    
22.
Charan J, Kaur RJ, Bhardwaj P, Haque M, Sharma P, Misra S, et al. Rapid review of suspected adverse drug events due to remdesivir in the WHO database; findings and implications. Expert Rev Clin Pharmacol 2021;14:95-103.  Back to cited text no. 22
    
23.
Kaur RJ, Charan J, Dutta S, Sharma P, Bhardwaj P, Sharma P, et al. Favipiravir use in COVID-19: Analysis of suspected adverse drug events reported in the WHO database. Infect Drug Resist 2020;13:4427-38.  Back to cited text no. 23
    
24.
Najar Nobari N, Seirafianpour F, Mashayekhi F, Goodarzi A A systematic review on treatment-related mucocutaneous reactions in COVID-19 patients. Dermatol Ther 2021;34:e14662.  Back to cited text no. 24
    
25.
Aslan Kayıran M, Cebeci F, Erdemir VA, Aksoy H, Akdeniz N, Gürel MS Fluorescence of nails and hair on wood’s lamp examination in Covid pandemic: Undefined effect of favipiravir in humans. Dermatol Ther 2021;34:e14740.  Back to cited text no. 25
    
26.
Gülseren D, Yalıcı-Armagan B Yellow-white fluorescence on the nails: A novel finding of favipiravir used for the treatment of COVID-19. J Cosmet Dermatol 2021;20:2392-3.  Back to cited text no. 26
    
27.
Guder H, Ozunal ZG Nail fluorescence in COVID-19 patients. JOJ Dermatol Cosmet 2021;3:79-82.  Back to cited text no. 27
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed263    
    Printed18    
    Emailed0    
    PDF Downloaded18    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]