Favipiravir
Favipiravir, sold under the brand name Avigan among others, is an antiviral medication used to treat influenza in Japan. It is also being studied to treat a number of other viral infections, including SARS-CoV-2. Like the experimental antiviral drugs T-1105 and T-1106, it is a pyrazinecarboxamide derivative.
It is being developed and manufactured by Toyama Chemical 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 in 2019.
Medical use
Favipiravir has been approved to treat influenza in Japan. It is, however, only indicated for novel influenza rather than seasonal influenza. 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. In one case report, a 6-month old infant developed benign bright blue discolouration of the cornea after treatment with favipiravir which resolved after treatment cessation.Mechanism of action
The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase. Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate, available in both oral and intravenous formulations. In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics. However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.[Image:Favipiravir-RTP structure.png|280px|thumb|left|Favipiravir ribofuranosyl triphosphate, the active form inside the body]
Favipiravir-RTP is a nucleoside analogue. It mimics both guanosine and adenosine nucleobases for viral RNA dependant RNA polymerase (RdRp). Incorporating two favipiravir ribofuranosyl bases in a row stops extension of the newly made RNA, although it is unclear how as of 2013.
Synthesis
There are multiple pathways to synthesize favipiravir. One synthesis starts with a pyrazine carboxylic acid, which is first reacted with thionyl chloride and then aqueous ammonia to produce 3-Hydroxypyrazine-2-carboxamide. The resulting material is nitrated with potassium nitrate and sulfuric acid to add a nitro group in the 6 position, which is then reduced using hydrazine hydrate to the corresponding amine. Finally, the amine is turned into a diazonium group using sodium nitrite and replaced with a fluorine group using hydrofluoric acid.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. 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. However, animal experiments show the potential for teratogenic 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 Avigan, Avifavir, Avipiravir, Areplivir, FabiFlu, Favipira, Reeqonus, and Qifenda.Use in Russia
Coronavir is the brand name of favipiravir used in Russia, where it is approved for the treatment of COVID-19. It is produced and sold by R-Pharm. Coronavir was approved for use in Russia in hospitals in July 2020, and in September 2020 it received approval for prescription sales for outpatient use. Avifavir, another drug also based on favipiravir, was earlier approved in May.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 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. A Cochrane Systematic review published in Feb 2024, noted that there is actually no real benefit with Favipiravir in treating Covid-19 in terms of mortality benefits, or admission to mechanical ventillation, or hospitalisation, and it may not make any difference in adverse effects or serious adverse effects., large-cohort clinical trials are underway.
Ebola
Research in 2014, suggested that favipiravir may have efficacy against Ebola based on studies in mouse models; 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 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, Guinea, in December 2014. Preliminary results presented in 2016 at the Conference on Retroviruses and Opportunistic Infections, 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 trial design was concomitantly criticised for using only historical controls.