Oral favipiravir for treatment of COVID-19: What is the current evidence of efficacy and safety?: Dr. Anant Patil
M3 India Newsdesk Jun 26, 2020
Dr. Anant Patil throws lights on various studies and trials that have tested the clinical efficacy and safety of the drug favipiravir, recently approved for the treatment of mild to moderate COVID-19 in India.
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The SARS-CoV-2 virus causing the coronavirus disease-19 (COVID-19) is an RNA virus. In order to fight the ongoing pandemic due to SARS-CoV-2 virus, there have been unprecedented developments in research worldwide. Research is pursued for both drugs and vaccines by different organisations.  Several antiviral drugs have been evaluated for their efficacy and safety in patients with COVID-19. Recently, favipiravir has attracted significant attention of healthcare professionals, media and general community in India.
What is favipiravir?
Favipiravir is a broad spectrum antiviral agent having activity against many RNA viruses including influenza virus and rhinovirus. It is licensed as an anti-influenza medicine in Japan. It has also been used for the treatment of other viral infections such as those caused by the Ebola virus and Lassa virus.
How does favipiravir work?
RNA-dependant RNA polymerase enzyme is required for the replication of RNA virus.  Favipiravir undergoes an intracellular phosphoribosylation to an active form, favipiravir-RTP and inhibits the RNA polymerase activity.  Favipiravir selectively and potently inhibits RNA-dependant RNA polymerase enzyme. [1,3] It does not have activity against DNA viruses. 
Evidence of efficacy and safety of Favipiravir in COVID-19
Few studies evaluating efficacy and safety of favipiravir have been published. In an open label, small study, Cai and colleagues  from China evaluated the effects of favipiravir (n=35) versus lopinavir/ritonavir (n=45) in laboratory-confirmed patients with COVID-19.
In one group, patients received favipiravir and interferon alpha. On day 1, favipiravir was given in the dose of 1600 mg twice daily whereas, from the second day onwards up to day 14, it was given in the dose of 600 mg twice daily. Interferon alpha aerosol inhalation was given in the dose of 5 million units, twice daily. In the second group, patients received lopinavir/ritonavir (400 mg/100 mg twice daily) and interferon alpha in the same dose.
The favipiravir group showed significantly shorter viral clearance time and significant improvement in chest imaging than lopinavir/ritonavir group. The incidence of adverse events was also lower in fevipiravir group (11.43% vs 55.56%; p<0.01). Small number of patients and no randomisation and blinding were some of the limitations of this study. 
In a prospective, randomised multicentre clinical trial, Chen and colleagues  from China compared the efficacy and safety of favipiravir versus arbidol in addition to conventional therapy in patients with COVID-19. A total of 120 patients were included in each group. Assessment was available for 116 and 120 patients in favipiravir and arbidol groups respectively. Favipiravir was given in the dose of 1600 mg twice on the first day followed by 600 mg twice daily from second day.
For ordinary patients with COVID-19, seven day's clinical recovery rate was significantly more in favipiravir group than arbidol group (71.43% vs 55.86%; p<0.0199). For critically ill patients (5.56 vs 0%; p=0.4712) and those with hypertension and/or diabetes (54.76% vs 51.43%; p=0.7704) there was no significant difference in seven days’ clinical recovery rate. Overall, there was no significant difference in the rate of overall adverse events in favipiravir versus arbidol groups (31.90% vs 23.33%; p=0.1410), but increase in serum uric acid was significantly more common in favipiravir group (13.79% vs 2.50; p = 0.0014). There was no significant difference for increase in liver enzymes in favipiravir and arbidol group (7.76% vs 10%; p=0.5455). Similarly, there was no significant different between two groups for psychiatric symptoms and gastrointestinal adverse events.
A preliminary report of Favipiravir Observational Study  (n=2158) in Japan is available online. In this study, out of 2141 patients, 1986 (92.8%) received two doses of 1800 mg on day one and 800 mg twice daily for subsequent days. The mean (standard deviation) duration of favipiravir (n=1672) was 10.4 (5.6) days. At day seven, rates of clinical improvement for mild and moderate disease were 73.8% and 66.6% respectively. At day 14, the rates were 87.8% and 84.5% respectively. For severe disease, the rates of clinical improvement at seven and 14 were 40.1% and 60.3% respectively. In this study, 24.65% patients reported adverse event. Hyperuricemia (15.52%) and liver function impairment (7.37%) were the two most common adverse events in the patients.
Few more trials are registered on Chinese Clinical Trial Registry (CHiCTR). The detailed results of multi-center phase 3 study evaluating the efficacy and safety of favipiravir in combination with standard supportive care in adult patients with mild to moderate COVID-19 will provide more insights for its efficacy and safety in Indian patients. [7,8] Another study planned for evaluation of combination of favipiravir and umifenovir versus favipiravir alone in hospitalized patients with moderate COVID-19 is also registered on clinical trial registry of India. 
Approval of favipiravir, a significant and positive development in India
Glenmark has received manufacturing and marketing approval as part of accelerated approval process. Approval of first oral favipiravir product for mild to moderate patients with COVID-19 is a significant and positive development in India. Currently, before using this medication, every patient is required to sign informed consent. The recommended dose of favipiravir for treatment of patients with mild to moderate COVID-19 is 1800 mg (9 tablets of 200 mg) twice daily on day 1, followed by 800 mg (4 tablets of 200 mg) twice daily up to day 14. 
Polytherapy is commonly expected in the treatment of COVID-19 considering comorbidities and complications in these patients. Favipiravir is metabolised in the liver mainly by aldehyde oxidase (AO) in the cytosol. Potential interactions with potent AO inhibitors and drugs metabolised by AO should be considered. 
Overall, approval of oral favipiravir for patients with mild to moderate COVID-19 patients in India is certainly a positive development. Details of results from clinical trials in India and experience by physicians will provide more insights about efficacy and safety of favipiravir in Indian patients.
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The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.
The author, Dr. Anant Patil is Assistant Professor of Pharmacology.
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