Adverse effects associated with favipiravir in patients with COVID-19 pneumonia: a retrospective study

ABSTRACT BACKGROUND: Favipiravir is generally used in treating coronavirus disease 2019 (COVID-19) pneumonia in Turkey. OBJECTIVE: To determine the side effects of favipiravir and whether it is a good treatment option. DESIGN AND SETTING: Retrospective study conducted in Atatürk Chest Diseases and Chest Surgery Training and Research Hospital, Ankara, Turkey. METHODS: 357 patients who completed favipiravir treatment at the recommended dose were included. 37 patients with drug side effects and 320 patients without drug side effects were examined in two groups. RESULTS: Side effects were observed in 37 (10.36%) out of 357 patients using favipiravir. The most common side effect was liver dysfunction, in 26 (7.28%) of the patients. The following other side effects were also observed: diarrhea (1.4%), nausea (0.84%), abdominal pain (0.28%) and thrombocytopenia (0.28%). One patient (0.28%) presented both increased transaminases and nausea. CONCLUSION: In this study, it was determined that favipiravir may constitute an alternative for treating COVID-19 pneumonia given that its side effects are generally well tolerated and not serious.

The effect of favipiravir versus hydroxychloroquine on clinical and laboratory findings in COVID-19 in healthcare workers

Abstract Objectives Comparative data on hydroxychloroquine and favipiravir, commonly used agents in the treatment of Coronavirus Disease-2019 (COVID-19), are still limited. In this study, it was aimed to compare treatment outcomes in healthcare workers with COVID-19 who were prospectively followed by the occupational health and safety unit. Methods A total of 237 healthcare-workers, diagnosed as mild or moderate COVID-19 between March 11, 2020 and January 1, 2021, were given hydroxychloroquine (n = 114) or favipiravir (n = 123). Clinical and laboratory findings were evaluated. Results The mean age of the patients was 33.4±11.5 years. The mean time to negative PCR was found to be significantly shorter in patients receiving favipiravir compared to the hydroxychloroquine group (10.9 vs. 13.9 days; p < 0.001). The rate of hospitalization in the hydroxychloroquine group was significantly higher than favipiravir group (15.8% vs. 3.3%). In terms of side effects; the frequency of diarrhea in patients receiving hydroxychloroquine was significantly higher than that in the favipiravir group (31.6% vs. 6.5%; p < 0.001). Conclusions Favipiravir and hydroxychloroquine were similar in terms of improvement of clinical symptoms of healthcare workers with mild or moderate COVID-19 infection, but favipiravir was significantly more effective in reducing viral load and hospitalization rates. Furthermore, favipiravir caused significantly less side-effects than hydroxychloroquine.

Favipiravir and its potentials in COVID-19 pandemic: An update

The COVID-19 pandemic has caused millions of deaths and hundreds of millions of confirmed infections worldwide. This pandemic has prompted researchers to produce medications or vaccines to reduce or stop the progression and spread of this disease. A variety of previously licensed and marketed medications are being tested for the treatment and recurrence of SARS-CoV2, including favipiravir (Avigan). Favipiravir was recognized as an influenza antiviral drug in Japan in 2014, and has been known to have a potential in vitro activity against SARS-CoV-2, in addition to its broad therapeutic safety scope. Favipiravir was recently approved and officially used in many countries worldwide. Our review provides insights and up-to-date knowledge of the current role of favipiravir in the treatment of COVID-19 infection, focusing on preclinical and ongoing clinical trials, evidence of its efficacy against SARS-CoV-2 in COVID-19, side effects, anti-viral mechanism, and the pharmacokinetic properties of the drug in the treatment of COVID-19. Due to its teratogenic effects, favipiravir cannot be offered to expectant or pregnant mothers. The practical efficacy of such an intervention regimen will depend on its dose, treatment duration, and cost as well as difficulties in application.

Guía de manejo clínico del paciente con infección por SARS-CoV-2 / Guidelines for clinical management of SARS-Cov-2 infection

Resumen En infección por SARS-CoV-2 (COVID-19), las manifestaciones más comunes son las de vías aéreas superiores; en casos complicados se presenta neumonía intersticial bilateral, insuficiencia respiratoria aguda grave y falla orgánica múltiple que ameritan tratamiento hospitalario y soporte ventilatorio por puntas nasales o mascarilla, así como oxígeno con flujo a presión alta o intubación orotraqueal y ventilación mecánica. No hay antivirales específicos por lo que el manejo es sintomático, así como con antiplaquetarios (ácido acetilsalicílico, dipiridamol), heparina de bajo peso molecular ante hipercoagulabilidad (dímero D aumentado), dexametasona ante indicadores altos de inflamación. Previo consentimiento informado, experimentalmente se emplean antibióticos según los resultados microbiológicos, interferón beta 1b, favipiravir, tocilizumab, ivermectina e inmunoglobulina G. Cuando se presenta gastroenteritis se puede indicar nitazoxanida.

Abstract In SARS-CoV-2 infection (COVID-19), the most common manifestations involve the upper airways; in complicated cases, bilateral interstitial pneumonia, severe acute respiratory failure and multiple organ failure occur, which require hospital treatment and ventilatory support with nasal cannula or mask and high flow oxygen, or orotracheal intubation and mechanical ventilation. There are no specific antivirals, and thus management is symptomatic, as well as with antiplatelet drugs (acetylsalicylic acid, dipyridamole), low molecular weight heparin when there is hypercoagulability (increased D-dimer), dexamethasone when inflammation indicators are elevated; experimentally, under informed consent, antibiotics are used according to microbiological results, as well as interferon beta 1b, favipiravir, tocilizumab, ivermectin and immunoglobulin G. When gastroenteritis occurs, nitazoxanide can be indicated.

The effects of favipiravir on hematological parameters of covid-19 patients

SUMMARY INTRODUCTION This study aims to evaluate changes in hematological parameters after the follow-up of patients who received treatment with favipiravir due to COVID-19 infections. METHODS Sixty-two cases receiving favipiravir treatment for at least five days due to COVID-19 infection were evaluated retrospectively. Parameters including age, gender, nasopharyngeal swab positivity, and chronic diseases were analyzed. Hematologic parameters were analyzed before and after the treatment. RESULTS The mean age of the patients receiving treatment with favipiravir was 63.7±12.3 years. Nasopharyngeal swab positivity was detected in 67.7%. The most common comorbid conditions detected in patients were hypertension in 25 cases (40.3%) and diabetes in 16 cases (25.8%). In the statistical analysis of the hematological parameters before and after treatment with favipiravir, WBC, PT-PTT-INR levels were found to be unaffected; the mean RBC was found to have decreased from 4.33 ± 0.58 M/uL to 4.16 ± 0.54 M/uL (p:0.003); the median hemoglobin level was found to have decreased from 12.3 g/dl to 11.9 g/dl (p:0.041); the hematocrit level decreased from 38.1% ± 4.8 to 36.9% ± 4.2 (p:0.026); the median neutrophil count decreased from 4.57 K/uL to 3.85 K/uL (p:0.001); the mean lymphocyte count increased from 1.22 ± 0.53 K/uL to 1.84 ± 1.19 K/uL (p:0.000); and the mean platelet count increased from 244.1 ± 85.1 K/uL to 281.9 ± 103.3 K/uL (p:0.005). CONCLUSION We concluded that the pathological effect of treatment with favipiravir on the hematologic system was the suppression in the erythrocyte series, and there were no adverse effects in other hematologic parameters.

RESUMO INTRODUÇÃO Este estudo tem como objetivo avaliar as alterações nos parâmetros hematológicos após o acompanhamento de pacientes que receberam tratamento com favipiravir devido à infecção por Covid-19. MÉTODOS Sessenta e dois casos em tratamento com favipiravir por pelo menos cinco dias devido à infecção por Covid-19 foram avaliados retrospectivamente. Parâmetros como idade, sexo, positividade do swab nasofaríngeo e doenças crônicas foram analisados. Os parâmetros hematológicos foram analisados antes e após o tratamento. RESULTADOS A idade média dos pacientes que receberam tratamento com favipiravir foi de 63,7±12,3 anos. A positividade do swab nasofaríngeo foi detectada em 67,7%. As condições comórbidas mais comuns detectadas nos pacientes foram hipertensão em 25 casos (40,3%) e diabetes em 16 casos (25,8%). Na análise estatística dos parâmetros hematológicos antes e após o tratamento com favipiravir, os níveis de leucócitos, PT-PTT-INR não foram afetados. Verificou-se que o RBC médio diminuiu de 4,33±0,58 M/uL para 4,16±0,54 M/uL (p=0,003); o nível médio de hemoglobina foi reduzido de 12,3 g/dl para 11,9 g/dl (p=0,041); o nível de hematócrito diminuiu de 38,1%±4,8 para 36,9%±4,2 (p=0,026); a contagem mediana de neutrófilos diminuiu de 4,57 K/uL para 3,85 K/uL (p=0,001); a contagem média de linfócitos aumentou de 1,22±0,53 K/uL para 1,84±1,19 K/uL (p=0,000); a contagem média de plaquetas aumentou de 244,1±85,1 K/uL para 281,9±103,3 K/uL (p=0,005). CONCLUSÃO Concluiu-se que o efeito patológico do tratamento com favipiravir no sistema hematológico foi a supressão na série eritrocitária e que não houve efeitos adversos em outros parâmetros hematológicos.

Inhibitory effect of favipiravir on canine distemper virus replication in vitro / 军事医学

Objective To investigate the inhibitory effect of favipiravir (T-705) on canine distemper virus (CDV) replication in Vero cells and DH82 cells.Methods The growth curves of CDV-11 strains from canine and CDV-3 strains from mink in Vero cells and DH82 cells were determined with indirect immunofluorescence assay and 50％ endpoint titration.The viability of Vero and DH82 cells was determined using the Cell Counting Kit-8.CDV inhibition at different concentrations of T-705 at different time points was measured .Results Cytotoxicity data showed that there was a moderate decline of viability in Vero cells after T-705 treatment, but no apparent cytotoxicity in DH 82 cells.T-705 significantly inhibited the replication of CDV-3 and CDV-11 in both Vero cells and DH82 cells in the test range of 2.441-1250 μg/ml. T-705 exhibited effective and stable antiviral activity when given at different time points post virus challenge .Conclusion Our results demonstrate that T-705 has effective antiviral activity and may be a promising anti-CDV drug candidate .

Simultaneous Determination of 5 Organic Solvents in Favipiravir by Headspace GC / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of 5 kinds residual ethanol,acetone,ethylacetate,N,N-diisopropylethylamine and toluene in favipiravir.METHODS:Headspace GC was adopted.The determination was performed on DB-624 capillary column,temperature programmed.The inlet temperature was 220 ℃,and detector was flame ionization detector with temperature of 250 ℃.Nitrogen was used as carrier gas at flow rate of 2.0 mL/min,split ratio was 10 ∶ 1,headspace equilibrium temperature was 80 ℃,equilibrium time was 20 min and headspace sample size was 1 mL.RESULTS:The linear range was 10.0-501.4 μg/mL for ethanol(r=0.999 9),10.0-501.4 μg/mL for acetone (r=0.999 9),10.1-502.6 μg/mL for ethylacetate (r=0.999 9),0.2-11.4 μg/mL for N,N-diisopropylethylamine (r=0.999 9)and 1.8-89.4 μg/mL for acetone(r=0.999 7).The limits of quantification were 5.3,3.4,5.2,6.1 and 20.4 μg/mL,and the limits of detection were 1.4,1.1,1.3,1.6,5.9 μg/mL.RSD of precision test was lower than 4.0％,and RSDs of acetone in stability and reproducibility tests were both lower than 4.0％.The recoveries were 96.61％-99.70％ (RSD=1.01％,n=9),95.81％-99.50％ (RSD=1.29％,n=9),96.42％-99.76％ (RSD=1.24％,n=9),96.36％-99.30％ (RSD=1.19％,n=9),97.00％-99.51％ (RSD=0.82％,n=9).CONCLUSIONS:The method is simple,accurate,reproducible and can be used for simultaneous determination of 5 organic solvents in favipiravir.

Synthesis of favipiravir / 国际药学研究杂志

Objective: To design and investigate an effective synthetic route of the antivirus compound favipiravir (T-705) with a stable and high yield. Methods: The commercial available diethyl aminomalonate hydrochloride was selected as the starting material. The product of aminolysis was cyclized with glyoxal to yield 3-hydroxy-2-pyraziamide, which was subjected to nitration with KNO3, chlorination and dehydration with POCl3 and fluorination with KF to afford 3, 6-difluoropyrazin-2-carbonnitrile. The difluorate product was further hydrolyzed and oxidized to give favipiravir. Results: The target compound was efficiently prepared by the above synthetic route. Conclusion: The reaction conditions are mild except the fluoro-substitution, in which all reagents should be dried completely. The synthetic procedure is simple, high-yield and suitable for scale preparation.

Synthesis of favipiravir / 国际药学研究杂志

Objective To design and investigate an effective synthetic route of the antivirus compound favipiravir(T-705) with a stable and high yield. Methods The commercial available diethyl aminomalonate hydrochloride was selected as the starting material. The product of aminolysis was cyclized with glyoxal to yield 3-hydroxy-2-pyraziamide, which was subjected to nitration with KNO3, chlorination and dehydration with POCl3 and fluorination with KF to afford 3, 6-difluoropyrazin-2-carbonnitrile. The difluorate product was further hydrolyzed and oxidized to give favipiravir. Results The target compound was efficiently prepared by the above synthetic route. Conclusion The reaction conditions are mild except the fluoro-substitution, in which all reagents should be dried completely. The synthetic procedure is simple, high-yield and suitable for scale preparation.