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.


INTRODUCTION
Since the first appearance of coronavirus disease 2019  in Wuhan, China, in December 2019, this disease has evolved into a global pandemic. 1 It is associated with a wide clinical spectrum of conditions, ranging from asymptomatic disease to fatal pneumonia. 2 Treatment protocols remain limited to guideline recommendations and clinical studies. No specific treatment or prophylaxis has been introduced for use.
Favipiravir is a purine analogue and ribonucleic acid (RNA)-dependent polymerase inhibitor that is used for influenza treatment in Japan. It has shown efficacy against many RNA viruses, including Ebola, neurovirus and Enterovirus. 3 It is generally considered safe, with good tolerability, low side-effect potential and a half-life of five hours. The reported side effects include diarrhea, elevated transaminase levels, hyperuricemia and neutropenia. 4

OBJECTIVE
In this study, we aimed to assess the side effects of favipiravir treatment among patients diagnosed with COVID-19 pneumonia, in order to discuss its role as a therapeutic option.

METHODS:
This retrospective study was conducted in Atatürk Chest Diseases and Chest Surgery Training and Research Hospital, Ankara, Turkey. The study included patients admitted to our hospital and hospitalized due to confirmed COVID-19, between September 1, 2020, and October 1, 2020.
COVID-19 was diagnosed using the reverse-transcription polymerase chain reaction (RT-PCR) test. In this retrospective study, data on clinical characteristics, along with laboratory and chest computed tomography (CT) findings, were retrieved from digital databases and patient files.
Patients > 18 years of age were deemed eligible if complete laboratory and chest CT data for them were available, along with a COVID-19 diagnosis via real-time RT-PCR; or if they showed highly suspicious disease based on clinical-radiological findings, despite RT-PCR negativity.
In accordance with the treatment guidelines for adult COVID-19 patients endorsed by the In addition, a few of the patients also had elevated baseline transaminases, but they were not excluded because transaminase levels could also be raised due to the disease itself.

Statistical analysis
Statistical analysis was performed using SPSS 25.0 (Statistical

RESULTS
Overall, 357 patients who completed the recommended favipiravir regimen were included. The patients were divided between those who did and those who did not experience drug side effects (n = 37 and n = 320, respectively). In both groups, males comprised the majority of cases (25/37, 67.6%; and 203/320, 63.4%, respectively). The mean ages in the two groups were comparable (62.88 ± 13.9 and 58.95 ± 13.08 years, respectively). Patients with favipiravir-related side effects had higher body mass index (BMI) (28.73 ± 4.51 versus 30.39 ± 4.76, P = 0.03) ( Table 1).
The most common comorbidities in both groups were hypertension and diabetes mellitus (DM). The most frequently used medications were oral anti-diabetics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs) and antiaggregating/anticoagulant agents. Patients without favipiravir-related side effects were more likely to be on ARB treatment (3/77; P = 0.04).  Figure 1).
A correlation analysis on determinants of favipiravir-related side effects showed that there were positive correlations with BMI and elevated baseline transaminase and ferritin levels; and negative correlations with elevated creatinine and ARB/ACEI use. However, all of these correlations were weak (r ≤ 0.2) ( Table 3). treatments in many countries, including Iran, Japan and China. [6][7][8][9] Favipiravir, an antiviral agent in the nucleotide-analogue class, has been approved for influenza treatment in Japan. Its activity profile against influenza, Ebola and many other RNA viruses has been established as consisting of prevention of viral replication via inhibition of viral RNA polymerase. 10 It is used as a pro-drug, with 94% bioavailability, 54% protein binding and low volume of distribution. Cmax (maximum concentration) is reached within two hours following a single dose, while both Tmax (maximum concentration time) and half-life increase after multiple doses.

DISCUSSION
It has a half-life of 2.5 to 5 hours and is metabolized via rapid renal elimination after hydroxylation, mainly through the action of aldehyde oxidase and marginally through xanthine oxidase. It exhibits dose-and time-dependent pharmacokinetic effects. While not metabolized by the cytochrome P450 (CYP) system, favipiravir inhibits one of the system's components (CYP 2C8). As such, caution is advised when it is co-administered with drugs metabolized by the CYP system. 11,12 The dose of favipiravir administered varies based on indication. For COVID-19, higher doses are generally preferred. 13,14 According to the national COVID-19 treatment guidelines issued by the Ministry of Health, a twice-daily dose of 1600 mg is recommended on the first day of treatment, followed by 600 mg, twice daily, for a total duration of 5 to 10 days, in patients with  In a Japanese study, 17 side effects were reported in 20% of the patients who received favipiravir in doses lower than those approved for COVID-19. Side effects were generally minor and, like in another study, 5 included hyperuricemia (5%), diarrhea (5%), neutropenia and elevated hepatic enzymes (2%). 17 In a review published in October 2020 that examined 32 studies registered at clinicaltrials.gov, elevated transaminase, eczema and pruritus, abdominal pain, nausea and diarrhea were reported in ≥ 1%, < 0.5%, 0.5%, 0.5 to 1% and ≥ 1% of the patients receiving favipiravir, respectively. 5 In the current study, the most common adverse effect was elevated transaminases (7.28%), with no cases of allergic side effects, while gastrointestinal disorders (abdominal pain, diarrhea and nausea) were found in lower proportions.
Since favipiravir is metabolized and inhibited by aldehyde oxidase, serum concentrations should be monitored and dosing should be adjusted in those with hepatic impairment. Favipiravir, or its metabolites, has been detected in semen and breastmilk. 11,12 Although favipiravir may have pharmacokinetic interactions with oseltamiver, its co-administration with acetaminophen in   While favipiravir inhibits CYP 2C8, significant side effects are unlikely, given that hydroxychloroquine is metabolized through multiple pathways. 19 This mechanism may explain the lack of difference between patients who received favipiravir alone and those who received favipiravir with hydroxychloroquine.
Favipiravir appears to be a good therapeutic option for treatment of COVID-19, as it can be administered orally and may also be given to symptomatic patients who do not require hospitalization. Like other antiviral agents, it may be recommendable to initiate favipiravir treatment soon after emergence of symptoms, given its ability to reduce viremia. This may certainly have some epidemiological implications in pandemics, such as in relation to COVID-19. Although side effects are generally well tolerated, laboratory parameters should be closely monitored.
The limitations of the present study were that it was conducted in a single center and had a retrospective design. This study was carried out in accordance with the recorded information only.
Thus, it was not easy to reach conclusions regarding risk factors, given that it is possible that not all of them were considered because of the nature of retrospective cohorts.

CONCLUSIONS
Favipiravir is a valuable drug for treatment of mild to moderately severe symptomatic COVID-19 patients. However, further randomized and controlled studies are warranted to provide more reassuring data for physicians regarding its use.