Potential of Favipiravir

in the Treatment of
COVID-19
What We Know So Far?

ERLINA BURHAN
DEPARTEMEN PULMONOLOGI DAN ILMU KEDOKTERAN RESPIRASI
FKUI-RSUP PERSAHABATAN / PERHIMPUNAN DOKTER PARU INDONESIA
 Epidemiology
EPIDEMIOLOGY

https://www.who.int/docs/default-source/coronaviruse/risk-comms-updates/update70_omicron.pdf?sfvrsn=eaf76988_5
 Epidemiology
EPIDEMIOLOGY

https://cdn.who.int/media/docs/default-source/searo/indonesia/covid19/external-situation-report-87_16-february-2022.pdf?sfvrsn=a5169f8b_5
 Antiviral Options for COVID-19 Treatment
RNA-dependent RNA polymerase (RdRp) genetic sequence from both COVID- ⮚ Early genome sequencing of
19 and SARS virion are 96% similar (especially at the active site)
2019-COV-2 virion showed that the virus
also expressed proteins that were already
known as drug targets in other viruses.

Repurposing of multiple antiviral drugs:

• Broad-spectrum antivirals
• Antivirals previously directed for SARS,
MERS, influenza, etc

• Morse J, et al. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. ChemBioChem. 2020;21:730–8
• Srinivasan K, Rao M. Understanding the clinical utility of favipiravir (T-705) in coronavirus disease of 2019: a review. Ther Adv Infectious Dis. 2021;8:1–6
 Favipiravir
ANTIVIRAL (FAVIPIRAVIR)

March 17, 2020, Director of National Biotechnology

In 2014, Oyama Chemical Co., Ltd. (Fujifilm)
Development in China said Avigan was found to be
announced a new drug that has been approved
effective in clinical studies during 2020.
by the Japanese Government, namely
➔ effective in treating corona-related symptoms
AVIGAN®Tablet 200mg. (Generic Name:
➔ no obvious side effects
Favipiravir; Development code: T-705)
➔ drug of choice to treat cases of COVID-19
➔ to treat influenza conditions
caused by SARS-CoV-2.

● Hackett DW. Carlson R. China Embraces Avigan, While Japan Studies. [Homepage on The Internet]. Cited March 11, 2021. Available on: https://www.precisionvaccinations.com/china-developing-generic-versions-avigan-favipiravir
● FujifilmToyama Chemical Co. Ltd. The New Drug Application Approval of “AVIGAN® Tablet 200mg” in Japan for the anti-influenza virus drug. [Homepage on The Internet]. Cited March 11, 2022. Available on:
http://fftc.fujifilm.co.jp/en/news/news140324e.html. (march 24, 2014).
 Mechanism of Action
MECHANISM OF ACTION

● Acts as a substrate for the RNA-

dependent RNA polymerase (RdRp)
enzyme to inhibit its activity leading to
termination of viral protein synthesis
● Gets incorporated in the viral RNA
strand, preventing further replication
● Induces lethal mutagenesis in vitro
during influenza virus infection (virucidal
drug)

● Agrawal U, Raju R, Udwadia ZF. Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India. 2020;76(4):370-6.
● Yanai H. Favipiravir: a possible pharmaceutical treatment for COVID-19. J Endocrinol Metab. 2020;10(2):33-4.
● Srinivasan K, Rao M. Understanding the clinical utility of favipiravir (T-705) in coronavirus disease of 2019: a review. Ther Adv Infectious Dis. 2021;8:1–6
Favipiravir for COVID-19: Viral Clearance (Meta-analysis)
● No. study: 4-5 ( 1.314 patients)
● Control group: antivirals
(liponavir, ritonavir, influenza
medications), hydrochloroquine,
supportive care

Result:
In patient with mild to
moderate COVID-19
symptoms, Favipiravir
treatment was associated
with higher viral clearance,
especially at day 10 after
treatment initiation
(RR= 1.1, 95% CI 1.0–1.3, p 0.04)

Deng W, et al. Evaluation of favipiravir in the

treatment of COVID-19 based on the real world.
Expert Rev. Anti-Infect. Ther. 2021;1–11
 Patients’ characteristic (N=55)
• Time from first negative PCR result
to re-positive : 20.6 ± 17.4 d
• 56% of patients had chronic disease
or tumor
• >80% of patients had a moderate
symptoms in the first positive PCR

Result:
• In re-positive patients,
Favipiravir was superior
to control in shortening
the duration of viral
shedding
(17 vs 26 days, p <0.05)

• Favipiravir group had a

higher viral clearance at
30 days than control
group
(81% vs 53 %, p <0.05)
 • Control Group :
Receive standard care

• Favipiravir Group:
Receive standard care
+ Favipiravir 1600 mg (bid) day 1,
600 mg (bid) day 2–7

(N=36) (N=19)

Result:
- After treatment with
Favipiravir, almost
all symptoms
disappeared. Only 1
patient had
persistent cough.
- In the control group,
most symptoms
persisted, especially
cough
Favipiravir for COVID-19: Clinical Improvements (Meta-analysis)
● No. study: 5-6 ( 816 patients)

● Control group: other antivirals

(liponavir, ritonavir, influenza
medications), hydrochloroquine,
supportive care

Result:
Favipiravir treatment was
associated with more
significant clinical
improvement after 7 days of
hospitalization compared to
control group
(RR= 1.2, 95% CI 1.1–1.4, p 0.001)

Hassanipour S, et al. The efficacy and safety of favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials. Sci Rep. 2021;11:11022
 The Viral Clearence of Covid-19 in Treatment with
Favipiravir
Systematic Review
and Meta-Analysis
of 9 Clinical Trials

The results of the meta-analysis:

Viral clearance was higher in the favipiravir

group vs. control after 14 days of hospitalization
(p = 0.094)

Hassanipour S et al. Sci Rep. 2021;11(1):11022.

 The Requiring Supplemental Oxygen Therapy in
Covid -19 Treatment with Favipiravir
Systematic Review
and Meta-Analysis
of 9 Clinical Trials

The results of the meta-analysis:

The need for supplemental oxygen therapy in

the favipiravir group was 7% less vs. control
group (p=0.664)

Hassanipour S et al. Sci Rep. 2021;11(1):11022.

 The Safety of Favipiravir in Treatment
of COVID-19
Systematic Review
and Meta-Analysis
of 9 Clinical Trials

The results of the meta-analysis:

1. Almost all adverse events of Favipiravir were

mild to moderate and in an equal or lower rate
compared to
the control groups.
2. The most prevalent adverse events included
nausea, vomiting, diarrhea, chest pain as well
as increase in serum liver transaminase and
uric acid levels.

Hassanipour S et al. Sci Rep. 2021;11(1):11022.

 Favipiravir for COVID-19: Length of Hospital Stay(Meta-analysis)

Result:
Favipiravir treatment was associated with reduced length of hospital stay Deng W, et al. Evaluation of favipiravir in the
treatment of COVID-19 based on the real world.
in studies with mild-moderate patients, but not in studies with severe Expert Rev. Anti-Infect. Ther. Dec 2021;1–11

patients
Favipiravir in Moderate-Severe COVID-19 Patients (Meta-analysis)
Forrest plot for the need for oxygen support or mechanical ventilation

Result:
Favipiravir treatment in
patients with moderate to
severe COVID-19
symptoms was not
associated with:
1. Decreased need for
Forrest plot for the rate of transfer to ICU oxygen
supplementation or
mechanical ventilation

2. Decreased rate of ICU

transfer

Deng W, et al. Evaluation of favipiravir in the treatment of COVID-19 based on the real world. Expert Rev. Anti-Infect. Ther. Dec 2021;1–11
Favipiravir for COVID-19: Mortality Risk (Meta-analysis)

Result:
Favipiravir treatment was not associated with reduced mortality risk
(both in studies with mild-moderate and severe patients)
Deng W, et al. Evaluation of favipiravir in the treatment of COVID-19 based on the real world. Expert Rev. Anti-Infect. Ther. Dec 2021;1–11
What The Guideline Say ?
Indonesia’s COVID-19 Management Guideline
4th Edition (January 2022)

Referensi :
 Indonesia’s COVID-19
Pharmacological Management of COVID-19 Guideline

Favipiravir is recommended for mild to severe COVID-19 patients.

 Favipiravir Guideline in Indonesia
FAVIPIRAVIR GUIDELINE IN INDONESIA

COVID-19 Severity Dose

Asymptomatic-mild First line therapy Day 1 1600 mg/12h

Day 2 to 5 600 mg/12h

Moderate Second line therapy Day 1 1600 mg/12h

Day 2 to 5 600 mg/12h

Severe Second line therapy Day 1 1600 mg/12h

Day 2 to 5 600 mg/12h

Burhan E, Susanto AD, Nasution SA, Ginanjar E, Pitoyo CW, Susilo A, et al, eds.. Pedoman Tatalaksana COVID-19 Edisi 4. Jakarta:PDPI, PERKI, PAPDI,
PERDATIN, IDAI: 2022
 Favipiravir Guideline in Indonesia
FAVIPIRAVIR GUIDELINE IN INDONESIA

Indications in Children Body weight Dose

● Alternatives when Remdesivir 10 - 15 kgs 500 mg/24h followed by 200

is not available mg/8h
● Mild - moderate COVID-19 16 - 21 kgs 800 mg/24h followed by 400
with comorbid/ mg/12h
immunocompromised
22 - 35 kgs 1200 mg/24h followed by 600
mg/12h
> 35kgs 1600mg/12h followed by 600
mg/12h

Burhan E, Susanto AD, Nasution SA, Ginanjar E, Pitoyo CW, Susilo A, et al, eds.. Pedoman Tatalaksana COVID-19 Edisi 4. Jakarta:PDPI, PERKI,
PAPDI, PERDATIN, IDAI: 2022
 Favipiravir in Indonesia

• No RCT has been

done in Indonesia

• Indonesian National
Food and Drug
Agency (BPOM)
released an
emergency use
authorization (EUA)
for Favipiravir usage in
October 2020

• Damayanti H, et al. The effectiveness and safety of favipiravir in COVID-19 hospitalized patients at tertiary referral hospital, Bali, Indonesia.
• BPOM. Tingkatkan angka kesembuhan dan turunkan angka kematian pasien COVID-19, Badan POM terbitkan izin penggunaan dalam kondisi darurat obat favipiravid dan remdesivir. Oct
2020 (cited March 2022). Available from: https://pom.go.id/new/view/more/pers/565/Tingkatkan-Angka-Kesembuhan-dan-Turunkan-Angka-Kematian-Pasien-COVID-19--Badan-POM-
Terbitkan-Izin-Penggunaan-dalam-Kondisi-Darurat-Obat-Favipiravir-dan-Remdesivir.html
 The Effectiveness of Favipiravir in Hospitalized
COVID-19 Patients (Indonesia)
Hospitalized Covid-19 patients with moderate to critical Covid-19 (>18 years old).

Favipiravir Group
n = 96 Outcome Parameter:
Observational Effectivity was measured by assessing
retrospective Non Favipiravir Group: the clinical condition at the end of the
study receive Remdesivir/Oseltamivir isolation period of 14 days
n = 36

Improvement in Clinical
Condition
P < 0,001
79.2%56.3% 43.8% The favipiravir group showed
100.0%
20.8% significant better clinical conditions
50.0%
0.0% than the non-favipiravir group
(79.2% vs. 56.3%)

Favipiravir Non-Favipiravir

Damayanti et al. Kesmas: Jurnal Kesehatan Masyarakat Nasional (National Public Health Journal). 2021; 16 (4):
 The Safety of Favipiravir in Hospitalized COVID-19
Patients (Indonesia)
Hospitalized Covid-19 patients with moderate to critical Covid-19 (>18 years old).

Favipiravir Group
Outcome Parameter:
Observational Safety was measured by assessing the
n = 96
retrospective Non Favipiravir Group: adverse events
study receive Remdesivir/Oseltamivir

n = 36

The most common adverse

events (AE) found in the use of
favipiravir were gastrointestinal
disturbances (12.5%).

Damayanti et al. Kesmas: Jurnal Kesehatan Masyarakat

Nasional (National Public Health Journal). 2021; 16 (4): 289-
 Efficacy of Favipiravir for Hemodialysis Patient
Infected with Covid-19
Case Report

52-year-old hemodialysis (3x/week for 3

years) patient infected with COVID-19

She had initially been treated with :

Lopinavir/ritonavir and ciclesonide for 5
days, but developed severe pneumonia
requiring invasive positive-pressure
ventilation

Those antiviral agents were subsequently

switched to favipiravir (3600 mg loading dose
followed by 1600 mg administered orally daily
in two divided doses) was administered for 2
weeks

She recovered gradually, and after 2 weeks was

extubated once the viral load of SARS-CoV-2 fell
below the limit of detection. Although
concentrations of several biliary enzymes were
elevated, no major adverse events were observed. Koshi E et al. CEN Case Reports. 2021;10:126-131
Research Updates:
Efficacy of Favipiravir toward COVID-19 mutant variants

Pharmaceutical technology. ChemRar’s avifavir demonstrate effectiveness again SARS-COV-2 variants. 2022 Jan (cited 2022 March). Available
from: https://www.pharmaceutical-technology.com/news/russia-avifavir-effectiveness-variants/
 Safety and Tolerability of Favipiravir (Meta-analysis)
Forrest plot for the rate of adverse events (AEs)

Reported Adverse Effects:

(From the most frequent)

• Gastrointestinal
symptoms
• Hyperuricemia
• Elevated liver enzymes
• Decreased neutrophil
count
• Increased blood
triglycerides
• Elevated creatinine
level
Result: • Psychiatric symptoms
- Most AEs from Favipiravir treatment were mild to moderate and self-limited • Chest pain
- The numbers of AEs observed between Favipiravir and control group were
comparable ( RR 0.77, 95% CI 0.34–1.7)

• Joshi S, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2021;102:501-8
• Hassanipour S, et al. The efficacy and safety of favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials. Sci Rep. 2021;11:11022
 Favipiravir
Indication Contraindication

● New or recurrent pandemic ● Should not be used in the first

influenza virus infection (limited trimester of pregnant women or
use for treatment in cases who are planning a pregnancy.
where other antiviral drugs are ● Hypersensitivity to all
not or less effective). components in favipiravir
● The preliminary results in Japan tablets
and China have shown good ● Severe hepatic or kidney
effectiveness. impairment
● The Indonesian Food and Drug Authority. Informatorium of COVID-19 Drugs in Indonesia. [Homepage on The Internet]. Cited March 9 2022.
Available on: https://www.pom.go.id/new/admin/dat/20201203/Informatorium_COVID-19_Indonesian_FDA_(english_version)_edit.pdf
● Joshi S, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2021;102:501-8
 Favipiravir

Warnings:
• Pregnancy test results must confirm negative prior to the treatment. If
pregnancy occurs during treatment --> stop immediately
• Breastfeeding women: stop breastfeeding because the active metabolite of
favipiravir is found in breast milk
• Distributed in sperm --> using effective contraceptive method until 7 days after
treatment ends, not having sexual relations with pregnant women

Teratogenicity were observed across all studies with fetal or

! embryo models across multiple animal species

● The Indonesian Food and Drug Authority. Informatorium of COVID-19 Drugs in Indonesia. [Homepage on The Internet]. Cited March 9 2022. Available on:
https://www.pom.go.id/new/admin/dat/20201203/Informatorium_COVID-19_Indonesian_FDA_(english_version)_edit.pdf
● Srinivasan K, Rao M. Understanding the clinical utility of favipiravir (T-705) in coronavirus disease of 2019: a review. Ther Adv Infectious Dis. 2021;8:1–6
 Favipiravir

Warnings:
• The administration with caution in
patients with gout or who have a history
of gout and hyperuricemia patients
• Influenza virus infections can be
accompanied by bacterial infection or can
be masked by influenza-like symptoms.
Give antibiotics if suspected
• Elderly patients: carefully conducted,
monitor general condition

● The Indonesian Food and Drug Authority. Informatorium of COVID-19 Drugs in Indonesia. [Homepage on The Internet]. Cited March 9 2022. Available on:
https://www.pom.go.id/new/admin/dat/20201203/Informatorium_COVID-19_Indonesian_FDA_(english_version)_edit.pdf
● Hase R, et al. Acute gouty arthritis during favipiravir treatment for coronavirus disease 2019. Intern Med. 2020;59:2327–9
 Favipiravir

Superiority
● More reasonable price than other drug of choice for COVID-19
● Rapid viral clearance as compared to Lopinavir/Ritonavir
● Easier to administer for asymptomatic and mildly ill people with COVID-19
● More accessible and affordable then other antiviral for COVID-19
→ alternative of Remdesivir.

● Joshi S, Parkar J, Ansari S, Vora A, Talwar D, Tiwaskar M, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2020:102:501-8.
● Manabe T, Kambayashi D, Akatsu H, Kudo K. Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis. BMC Infect Dis.
2021:21(1):489.
 FAVIPIRAVIR MOLNUPIRAVIR
How supplied Tablet 200 mg Capsule 200 mg
Indications of COVID-19 Mild to moderate Mild to moderate
(BPOM) (BPOM & USFDA)
Indonesia’s Mild to severe
COVID-19 Guideline
User age Adult (≥18 years old) Adult (≥18 years old) who do not require oxygen
administration and are at risk of worsening.
Dose Day 1: 2 x 8 tablet/days 2 x 4 capsules/days
Day 2 etc: 2 x 3 tablet/days
Duration 5 days 5 days
Renal impairment Severe impairment: use with caution Severe impairment: use with caution
Hepatic impairment use with caution Severe impairment: use with caution
Pregnancy Contraindicated Contraindicated
Breastfeeding Breastfeeding should be stopped Breastfeeding should be stopped while taking the
drug up to 4 days after the last dose.
Pediatric Indonesia’s COVID-19 Guideline: Can be given for Not permitted for <18 years old because it can affect
patient with BW ≥10 kg bone growth.
Efficacy Clinical improvement after 7 days of hospitalization Early therapy was effective reduced risk of
was more remarkable than other drugs.(Hassanipour S et hospitalization or death by 31% vs placebo.(MOVe-OUT)
al.)

Efficacy against variant Consistent antiviral effect (in vitro) against Delta & Consistent antiviral effect (in vitro) against Delta &
Omicron. Omicron
 Summary

● Favipiravir was originally used to treat influenza, but is currently effective in treating COVID-
19
● Favipiravir has a strong efficacy for treating COVID-19 patients with mild-moderate illness
● Recent evidence support the safety and tolerability of short-term Favipiravir administration
● Favipiravir is more accessible than other antiviral.
● Despite the evidence of its safety, Favipiravir is not recommended for pregnant or
breastfeeding women.
● Caution in administration of Favipiravir for people with hyperuricemia or gout