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Favipiravir, sold under the brand name Avigan among others, is an
antiviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do ...
used to treat
influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
in Japan. It is also being studied to treat a number of other viral infections, including
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
. Like the experimental antiviral drugs T-1105 and T-1106, it is a pyrazinecarboxamide derivative. It is being developed and manufactured by Toyama Chemical (a subsidiary of
Fujifilm , trading as Fujifilm, or simply Fuji, is a Japanese multinational conglomerate headquartered in Tokyo, Japan, operating in the realms of photography, optics, office and medical electronics, biotechnology, and chemicals. The offerings from th ...
) and was approved for medical use in Japan in 2014. In 2016, Fujifilm licensed it to Zhejiang Hisun Pharmaceutical Co. It became a
generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
in 2019.


Medical use

Favipiravir has been approved to treat
influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
in Japan. It is, however, only indicated for novel influenza (strains that cause more severe disease) rather than
seasonal influenza Flu season is an annually recurring time period characterized by the prevalence of an outbreak of influenza (flu). The season occurs during the cold half of the year in each hemispheres of Earth, hemisphere. It takes approximately two days to ...
. As of 2020, the probability of resistance developing appears low.


Side effects

There is evidence that use during pregnancy may result in harm to the baby. Teratogenic and embryotoxic effects were shown on four animal species.


Mechanism of action

The mechanism of its actions is thought to be related to the selective inhibition of viral
RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to t ...
. Favipiravir is a
prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations. In 2014, favipiravir was approved in Japan for stockpiling against
influenza pandemic An influenza pandemic is an epidemic of an influenza virus that spreads across a large region (either multiple continents or worldwide) and infects a large proportion of the population. There have been six major influenza epidemics in the last ...
s. However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment. Favipiravir-RTP is a
nucleoside analogue Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates. Nucleoside and nucl ...
. It mimics both guanosine and adenosine for the viral RdRP. Incorporating two such bases in a row stops primer extension, although it is unclear how as of 2013.


Society and culture


Legal status

The US Department of Defense developed favipiravir in partnership with MediVector, Inc. as a broad-spectrum antiviral and sponsored it through FDA Phase II and Phase III clinical trials, where it demonstrated safety in humans and efficacy against the influenza virus. Despite demonstrating safety in more than 2,000 patients and , favipiravir remains unapproved in the UK and the USA. In 2014, Japan approved favipiravir for treating influenza strains unresponsive to current antivirals. Toyama Chemical initially hoped that favipiravir would become a new influenza medication that could replace
oseltamivir Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at high ...
(brand name Tamiflu). However, animal experiments show the potential for
teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...
effects, and the approval of production by The Ministry of Health, Labor and Welfare was greatly delayed and the production condition is limited only in an emergency in Japan. Despite limited data on efficacy, as of March 2021 favipiravir is widely prescribed for outpatient treatment of mild to moderate COVID-19 in Egypt, Hungary and Serbia. Patients are required to sign a consent form before obtaining the drug.


Brand names

Favipiravir is sold under the brand names , Avifavir, Avipiravir, Areplivir, FabiFlu, Favipira, Reeqonus, and Qifenda.


Research


COVID-19

Favipiravir, as an antiviral drug, has been authorized for treating COVID-19 in several countries including Japan, Russia, Serbia, Turkey, India, and Thailand, under emergency provisions. A rapid meta-review in September 2020 (analyzing four studies) noted that the drug led to clinical and radiological improvements; however, no reduction in mortality or differences in oxygen-support requirement were observed and more rigorous studies were sought. , large-cohort clinical trials are underway.


Ebola

Research in 2014, suggested that favipiravir may have efficacy against
Ebola Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after becom ...
based on studies in
mouse model A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...
s; efficacy in humans was unaddressed. During the 2014 West Africa Ebola virus outbreak, a French nurse who contracted Ebola while volunteering for
Médecins Sans Frontières (MSF; pronounced ), also known as Doctors Without Borders, is a humanitarian medical non-governmental organisation (NGO) or charity of French origin known for its projects in conflict zones and in countries affected by endemic diseases. M ...
(MSF) in Liberia reportedly recovered after receiving a course of favipiravir. A clinical trial investigating the use of favipiravir against Ebola virus disease began in
Guéckédou Guéckédou or Guékédou is a town in southern Guinea near the Sierra Leone and Liberian borders. It had a population of 79,140 in 1996 (census) but has grown massively since the civil wars and, , it is estimated to be 221,715. It was a centre o ...
, Guinea, in December 2014. Preliminary results presented in 2016 at the
Conference on Retroviruses and Opportunistic Infections The Conference on Retroviruses and Opportunistic Infections (CROI) is an annual scientific meeting devoted to the understanding, prevention and treatment of HIV/AIDS and the opportunistic infection An opportunistic infection is an infection ca ...
(CROI), later published, showed a decrease in mortality in patients with low-to-moderate levels of virus in blood, but no effect on patients with high levels (the group at a higher risk of death). The trial design was concomitantly criticised for using only historical controls.


Nipah

Nipah virus Nipah virus, scientific name ''Nipah henipavirus'', is a bat-borne virus that causes Nipah virus infection in humans and other animals, a disease with a high mortality rate. Numerous disease outbreaks caused by Nipah virus have occurred in Sout ...
is a causative agent of outbreaks of encephalitis with pneumonia and has a high
case fatality rate In epidemiology, case fatality rate (CFR) – or sometimes more accurately case-fatality risk – is the proportion of people diagnosed with a certain disease, who end up dying of it. Unlike a disease's mortality rate, the CFR does not take int ...
. The first outbreak occurred in Malaysia-Singapore, related to contact with pigs in slaughterhouses and an outbreak in Philippines related to slaughter of horses, most other outbreaks have affected India and Bangladesh. in Bangladesh outbreaks are often associated with consumption of raw date palm sap contaminated by saliva and urine of fruit bats. In a study published in the Scientific Reports, Syrian hamster model for Nipah virus infection was used, which closely mirrors most aspects of human disease, such as widespread vasculitis, pneumonia, and encephalitis. The hamsters were infected with a lethal dose of 104 PFU NiV-M via the intraperitoneal (i.p.) route similar to previous studies and treatment was initiated immediately after infection. Favipiravir was administered twice daily via the peroral (p.o.) route for 14 days. The treated hamsters displayed 100% survival and no obvious morbidity after lethal NiV challenge, whereas all the control cases died of severe disease.


Other

In experiments in animals favipiravir has shown activity against
West Nile virus West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family ''Flaviviridae'', from the genus ''Flavivirus'', which also contains the Zika virus, dengue virus, and yellow fever virus. The virus ...
,
yellow fever virus Yellow fever is a viral disease of typically short duration. In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains – particularly in the back – and headaches. Symptoms typically improve within five days. In ...
,
foot-and-mouth disease virus ''Foot-and-mouth disease virus'' (FMDV) is the pathogen that causes foot-and-mouth disease. It is a picornavirus, the prototypical member of the genus ''Aphthovirus''. The disease, which causes vesicles (blisters) in the mouth and feet of cattl ...
as well as other
flavivirus ''Flavivirus'' is a genus of positive-strand RNA viruses in the family ''Flaviviridae''. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other viruses which may cau ...
es,
arenavirus An arenavirus is a bisegmented ambisense RNA virus that is a member of the family ''Arenaviridae''. These viruses infect rodents and occasionally humans. A class of novel, highly divergent arenaviruses, properly known as reptarenaviruses, have ...
es,
bunyavirus ''Bunyavirales'' is an order of segmented negative-strand RNA viruses with mainly tripartite genomes. Member viruses infect arthropods, plants, protozoans, and vertebrates. It is the only order in the class ''Ellioviricetes''. The name ''Bunyavi ...
es and
alphavirus ''Alphavirus'' is a genus of RNA viruses, the sole genus in the ''Togaviridae'' family. Alphaviruses belong to group IV of the Baltimore classification of viruses, with a positive-sense, single-stranded RNA genome. There are 32 alphaviruses ...
es. Activity against
enterovirus ''Enterovirus'' is a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are named by their transmission-route through the intestine ('enteric' meaning intestinal). Serologic ...
es and Rift Valley fever virus has also been demonstrated. Favipiravir has showed limited efficacy against
Zika virus ''Zika virus'' (ZIKV; pronounced or ) is a member of the virus family ''Flaviviridae''. It is spread by daytime-active ''Aedes'' mosquitoes, such as '' A. aegypti'' and '' A. albopictus''. Its name comes from the Ziika Forest of Uganda, whe ...
in animal studies, but was less effective than other antivirals such as MK-608. The agent has also shown some efficacy against
rabies Rabies is a viral disease that causes encephalitis in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, vi ...
, and has been used experimentally in some humans infected with the virus.


Tautomerism

The possible
tautomerism Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...
of favipiravir has been investigated computationally. It was found that the enol-like form was substantially more stable in aqueous solution than the keto-like form, meaning that Favipiravir likely exists almost exclusively in the enol-like form in aqueous solution. Upon protonation the keto form is switched on. However these findings were caveated with the need to confirm this experimentally. File:Avigan-enol.jpg, Enol-like tautomeric form File:Avigan-keto.jpg, Keto-like tautomeric form


References


External links

* {{Portal bar , Medicine , Viruses Anti–RNA virus drugs Pyrazines Carboxamides Organofluorides Ebola Hydroxyarenes Experimental drugs Isomerism COVID-19 drug development