Favipiravir (259793-96-9)

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Description

1. Introduction

Favipiravir (259793-96-9) is an oral anti-viral drug used in the treatment of influenza virus in Japan. Favipiravir was first discovered in a laboratory screening for potential anti-viral properties against the influenza virus by Toyama Chemical Company, Ltd.

Favipiravir a prodrug, is converted intracellularly into its active form (favipiravir-RTP) in cells, and thus perceived as a substrate by virus RNA polymerase which inhibits RNA polymerase activity. It is hence speculated for treatment of COVID-19 (an RNA virus).

Coronavirus disease 2019 (COVID-19) is a serious disease caused by severe acute respiratory syndrome coronavirus 2. The first case was officially announced in December 2019 in Wuhan, China. This disease has spread to many parts of the world and was declared a pandemic by the World Health Organization (WHO) in March 2020. The most familiar symptoms are fever, dry cough, shortness of breath, fatigue, and insensitivity to smell and taste. But these can advance to acute respiratory distress syndrome (ARDS). This virus is mostly passed on through close contact with infected persons. Health officials recommend proper hand hygiene, physical distance from others, quarantine, avoiding unnecessary facial touch and use of face masks as measures to curb the disease.

There are no vaccines nor antiviral drugs fully approved for treatment of this infectious disease, COVID-19, according to the World Health Organization (WHO). The current fight against this disease involves isolation of infected persons, treatment of symptoms, additional care and some undergoing experimental techniques.

Research on vaccines and medication for COVID-19 is ongoing by government agencies, academic officials and industrial institutions worldwide. The current research is based on re-purposing the existing antiviral drugs for potential activity against COVID-19. Favipiravir is one of the most promising antiviral agent against the COVID-19.

Favipiravir (259793-96-9) Specifications

CAS 259793-96-9
CAS Min % 98%
CAS Max % 100%
MDL Number MFCD12032148
InChI Key FC1=CNC(C(C(N)=O)=N1)=O
Chemical Name or Material 6-Fluoro-3,4-dihydro-3-oxo-2-pyrazinecarboxamide; 6-Fluoro-3,4-dihydro-3-oxo-pyrazinecarboxamide; 6-Fluoro-3-hydroxy-2-pyrazinecarboxamide; Favipiravir; T 705; T 705 (Pharmaceutical)
Infrared Spectrum Authentic
Physical Form Powder
Packaging Aluminum Foil Bag
Molecular Formula C5H4FN3O2
Molecular Weight (g/mol) 157.1025632
SMILES ZCGNOVWYSGBHAU-UHFFFAOYSA-N
Color White powder
Melting Point >151°C (dec.)
Assay 98%

2. What Is Favipiravir

Favipiravir (259793-96-9) is a broad-spectrum oral antiviral agent approved for cure of all the sub-types of influenza (A, B, and C). Favipiravir also referred to as T-705, is a selective but effective inhibitor of the RNA polymerase, an enzyme responsible for viral synthesis and replication.

Favipiravir (T-705), a guanine derivative is an effective inhibitor of the RNA-dependent RNA polymerase of many RNA viruses such as influenza, yellow fever, Ebola, chikungunya, norovirus and enterovirus. Recently, some studies report its antiviral activity against the New-Coronavirus pneumonia known as COVID-19.

3. Favipiravir Mechanism of action

Favipiravir mechanism of action is related to the selective inhibition of viral RNA polymerase. It acts by competing with purine nucleosides and disrupts viral replication in the RNA virus. This, hence explains its potential in inhibiting the RNA -dependent RNA polymerase of many RNA viruses.

Some studies also suggest that favipiravir induces RNA mutations which results to a non-viable viral phenotype.

It should be noted that most antiviral drugs require early use in order to effectively control the rate of viral replication. This is because, viral replication can slow down in the later stages of the disease resulting to other issues as the body’s immune system responds rapidly and could lead to organ failure.

Favipiravir is selective and hence does not block RNA or DNA synthesis in the cells of mammals and also its non-toxic to them.

4. Favipiravir Effects

Favipiravir effects against various RNA viruses is evident. It has been seen to possess anti-viral activity against influenza viruses, yellow fever virus, Ebola, West Nile virus, foot and mouth disease virus, and also against flaviviruses, bunya viruses, arenaviruses, and alphaviruses. It also has some effects on enteroviruses and Rift Valley fever virus but has limited effects on Zika virus as tested using animal models.

i. Favipiravir for Ebola treatment

During the 2014-2015 Ebola virus outbreak in West Africa, a nurse who was a French national contracted the Ebola virus while working as a volunteer for Medecins Sans Frontires (MSF) in Liberia. The nurse was reported to recover after receiving favipiravir. This lead to research on favipiravir as a potential Ebola treatment.

The efficacy of favipiravir against Ebola virus was tested in a mouse model.  It was reported that early favipiravir treatment was effective, but the curative action of favipiravir may be limited in individuals with advanced infections.

A human clinical favipiravir trial against Ebola virus disease was commenced in Guinea, in December 2014. The preliminary findings were that favipiravir significantly decreased the mortality of patients with mild to moderate viral infections but no effect on persons with high level of Ebola infection. It has since been registered for treatment of Ebola disease.

ii. Favipiravir for treatment of influenza

Influenza virus is an RNA virus with three types, A, B, and C, are known to exist. It basically infects the respiratory pathway leading to fever, fatigue and one could recover in a week’s time. However, in vulnerable groups such as newborns, elderly and persons with other conditions such as cardiac illness and diabetes, influenza could lead to severe illness and death may occur.

Invitro studies revealed the potential antiviral activity of favipiravir against the influenza virus. Animal models using mouse infected with the influenza virus showed that favipiravir at 30 mg/kg/day or more prevented death, hindered lung congestion and lead to a lower virus capacity in the lungs.

iii. Favipiravir for treatment of COVID-19

Favipiravir is currently the most promising antiviral candidate for the treatment for COVID-19. Favipiravir trials have been conducted worldwide and preliminary studies show that it has potential effects against the disease. Some clinical studies are still ongoing to fully determine the potential of this drugs. Some of the favipiravir trials conducted include;

Favipiravir Trial for COVID-19 in China

In February 2020, a study with 80 persons was conducted to assess favipiravir for the treatment of COVID-19 in comparison with lopinavir/ritonavir. The results indicated that favipiravir had more antiviral activity than lopinavir/ritonavir. It was found to decrease the time of viral clearance and also enhanced CT-scans in more than 80% of the patients with few side effects. However, this study was not randomized and was without a control.

In a randomized clinical study, favipiravir was indicated an effective treatment for COVID‐19. When tested on ordinary individuals with COVID‐19, favipiravir treatment was found to increase the 7 day’s clinical recovery rate from 55.86% to 71.43%. The time of fever and cough relief was found to decrease substantially for ordinary participants with COVID‐19 and patients with conditions such as hypertension and/or diabetes in the favipiravir treatment group.

Favipiravir Trial for COVID-19 in Russia

A clinical study with 40 participants was conducted to assess the efficacy of favipiravir. it was found that 60% of the patients recovered from COVID-19 after five days of treatment which was two times higher than the patients on the recommended therapy.

Favipiravir has been reported to decrease the duration of viral clearance by more than half from 9 days with the standard therapy to 4 days with the Avifavir drug. It was noted to have 80% efficacy as an antiviral drug.

Russia has registered the first covid-19 drug, Avifavir (which is a drug based on Favipiravir) in the world. This is after an evidence of the safety of the drug with no reported adverse side effects.

– Favipiravir Trial for COVID-19 in Japan

Japan’s health officials have also embraced favipiravir trials against COVID-19. They, however, emphasized the efficacy was noted on patients with mild to moderate symptoms. There have been some reports stating that it is not as effective when administered to patients with severe symptoms.

 – Favipiravir Trial for COVID-19 in India

Clinical trials involving favipiravir and umifenovir have shown the efficacy of these drugs in inhibiting the virus invitro and also against the COVID-19 virus.

Basically, favipiravir is an oral antiviral medication approved in Japan in 2014 for the treatment influenza virus. It acts primarily by inhibiting viral replication.

Umifenovir is on the other hand, is also an oral antiviral agent approved for the treatment and prevention of influenza virus in Russia and China. This drug hinders viral attachment to cells and also acts to inhibit viral entry. It also acts to regulate the immune system and induces the production of interferon (a protein that inhibits viral replication).

Therefore, a combination of Favipiravir and Umifenovir with different mechanism of action offers an all-inclusive antiviral cover for both pre-entry and post-entry life cycle of the virus that causes COVID-19.

Trials are being initiated on a combination of these two antiviral drugs with an argument that the early administration of these medications with different mechanisms is needed for the treatment of COVID-19. This is because the viral load of COVID-19 virus is at peak during the time the first symptom appear.

-Others

Favipiravir has also been proven to be effective against; 

  • West Nile virus
  • Yellow fever virus
  • Arenavirus and bunya virus
  • Foot-and-mouth disease virus
  • Alphaviruses
  • Poliovirus, rhinovirus, and respiratory syncytial virus (RSV)
  • Bovine viral diarrhea virus (BVDV),
  • Hepatitis C virus (HCV)

6. Favipiravir dosage for COVID-19

The dosage rate of a drug is of paramount importance and that does not exempt antiviral drugs. Since scientists around the world are researching on the possible drugs for treatment of COVID-19 virus, the favipiravir dosage in the existing uses form basis for the current clinical trials.

Favipiravir dosage for Influenza

The approved favipiravir dosage for influenza in Japan is 3,200 mg oral loading dose given twice daily at 1,600 mg after every 12 hours on day 1, then 600 mg twice daily on days 2–5 of treatment. A higher dosage of 1,800 mg twice daily on day 1 then 800 mg twice daily has been used in advanced clinical trials.

Favipiravir dosage for Ebola

The dose of favipiravir used in the treatment of patients with Ebola virus infection is 6000 mg (given at 2,400 mg, 2,400 mg and 1,200 mg every 8 hours) on the first day followed by 2400 mg/day at 1,200 mg twice daily on day 2-9 of the treatment.

Favipiravir dosage for COVID-19

Since the favipiravir trials are still preliminary, there is no conclusive recommended dosage for treatment of the coronavirus. However, a few dosages have been used effectively in the clinical trials without adverse effects.

According to the clinical trial in China, a dose of 3,200 mg (1,600 mg twice daily) on the first day1 followed by 1,200 mg at 600 mg twice daily on the 2nd to 14th day is effective.

A recommended dose of 1,800 mg twice daily on day 1, followed by 800 mg twice daily up to day 14, has been prescribed in the registered product FabiFlu (favipiravir) in India.

However, this dosage is not conclusive since several trials are still ongoing.

 7. Favipiravir Side Effects

Although, no adverse Favipiravir side effects have been reported in the preliminary results, Favipiravir has been discouraged for use in pregnant women due to its embryo toxicity and teratogenicity shown in animals.

The main adverse effects that could occur due to use of favipiravir include moderate diarrhea, an asymptomatic rise of blood uric acid and transaminases, and a lower neutrophil counts.

8. Favipiravir approval status

There is no medication or vaccine is fully approved specifically to treat the disease, COVID-19. However, scientists around the world are working towards development of a viable treatment of the disease.

Favipiravir has received much attention as a candidate for treatment of COVID-19 worldwide. The drug has been approved for use in clinical trials across many countries including; China, Italy, Japan, Russia, London, and India.

The drug (Avifavir which is favipiravir based) has been recently approved for the treatment of COVID-19 in hospital settings in Russia on May 29, 2020. However, the Ministry of Health has only issued a temporary certificate subject to further ongoing clinical trials.

Favipiravir has also been approved in India by the brand name FabiFlu.

References:

  1. Du YX, Chen XP (April 2020). “Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection”. Clinical Pharmacology and Therapeutics. doi: 1002/cpt.1844. PMID32246834.
  2. Guedj J, Piorkowski G, Jacquot F, Madelain V, Nguyen TH, Rodallec A, et al. (March 2018). “Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques”.  PLOS Medicine.  15(3): e1002535.  doi: 11371/journal. pmed.1002535.  PMC 5870946.  PMID 29584730.
  3. DelhiJune 20, India Today Web Desk New; June 20, 2020 UPDATED; Ist, 2020 22:30. “Glenmark’s FabiFlu approved for coronavirus treatment in India, costs Rs 103 per tablet”. India Today. Retrieved 2020-06-21.
  4. Furuta, Y., Komeno, T., & Nakamura, T. (2017). Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proceedings of the Japan Academy. Series B, Physical and biological sciences93(7), 449–463.

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This product(s) resides on a APICMO contract.

The ability to produce, synthesize and manufacture large quantities of Favipiravir (259793-96-9) with quality control system under CGMP manufacturing
regulations.