Why Choose
Favipiravir?

Antiviral Drug Favipiravir is a broad-spectrum inhibitor of viral RNA polymerase, an enzyme required for viral replication when human host cells are infected. It is also used to treat Influenza and it has been investigated in other countries to treat novel viruses including Ebola and recently, COVID-19.

ENQUIRE  

The 2019 coronavirus disease (COVID-19) incidence and mortality are rapidly climbing and the treatment options are limited. There is a need of new therapeutic options but it is limited by a lack of evidence and time required for development. Since there is no licensed treatment that specifically acts against COVID-19, medications such as broad-spectrum antivirals are being studied as experimental adjuncts to supportive care. SARS-CoV-2 and influenza viruses show similar disease presentations and similar organ trophism.

About Favivir

FAVIVIR contains Favipiravir. Favipiravir is a novel antiviral compound that selectively and potently inhibits the RNA dependent RNA polymerase (RdRP) of influenza and many other RNA viruses. It has been found to inhibit all serotypes and strains of influenza A, B and C viruses against which it has been tested, including those resistant to other therapies. Favipiravir is currently the drug under investigation for COVID-19.

favivir

Favipiravir is an investigational product and is considered for use in the treatment of coronavirus infection. The Drug Controller General of India (DCGI) has granted an accelerated approval of this drug to meet the urgent medical need for the treatment of COVID-19 through restricted medical use.

Composition

Each film coated tablet contains : Favipiravir 200 mg, Excipients q.s.

Indications

Favipiravir is indicated for the treatment of mild to moderate COVID-19 disease.

Dosage and administration

The usual dosage of Favipiravir for adults is 1800 mg orally twice daily for 1 day followed by 800 mg orally twice daily up to maximum of 14 days.

Contraindications

  • Women known or suspected to be pregnant (Early embryonic deaths and teratogenicity have been observed in animal studies).
  • Patients with a history of hypersensitivity to any ingredient of the drug.
  • Patients with severe renal and hepatic impairment.

Warnings And Precautions

  • Since early embryonic deaths and teratogenicity have been observed in animal studies for favipiravir, do not administer the drug to women known or suspected to be pregnant. When administering favipiravir to women of child-bearing potential, confirm a negative pregnancy test result before starting the treatment. Explain fully the risks and instruct thoroughly to use most effective contraceptive methods with her partner during and for 7 days after the end of the treatment. If pregnancy is suspected during the treatment, instruct to discontinue the treatment immediately and to consult a doctor.
  • Favipiravir is distributed in sperm. When administering the drug to male patients, explain fully the risks and instruct thoroughly to use most effective contraceptive methods in sexual intercourse during and for 7 days after the end of the treatment (men must wear a condom). In addition, instruct not to have sexual intercourse with pregnant women.
  • Prior to the treatment, explain thoroughly the efficacy and risks (including the risk of exposure to fetus) in writing to patients or their family members and obtain their written consent.
  • Examine carefully the necessity of favipiravir before use.
  • Favipiravir is a drug the use of which is considered only when there is an outbreak of novel or re-emerging influenza virus infections in which other anti-influenza virus agents are not effective or insufficiently effective and the government decides to use the drug as a counter measure against such influenza viruses. When administering the drug, obtain the latest information including government's direction of counter measures against such influenza viruses, and prescribe only to appropriate patients.
  • Favipiravir is not effective against bacterial infections
  • Favipiravir has not been administered to children.
  • Careful Administration Favipiravir should be administered with care in the patients with gout or a history of gout, and patients with hyperuricaemia Blood uric acid level may increase, and symptoms may be aggravated.
  • No clinical study has been conducted to examine the efficacy and safety of favipiravir with the approved dosage. The approved dosage was estimated based on the results of a placebo-controlled phase I/II clinical study in patients with influenza virus infection and the pharmacokinetic data from Japanese and overseas studies. Favipiravir is not studied in SARS-CoV-2 positive patients with comorbid conditions.
  • Although the causal relationship is unknown, psychoneurotic symptoms such as abnormal behavior after administration of anti-influenza virus agents including favipiravir have been reported. For the treatment of children and minors, as a preventive approach in case of an accident due to abnormal behavior such as fall, patients / their family should be instructed that, after the start of treatment with anti-influenza virus agents, abnormal behavior may be developed, and guardians and others should make an arrangement so that children / minors are not left alone for at least 2 days when they are treated at home. Since similar symptoms associated with influenza encephalopathy have been reported, the same instruction as above should be given.
  • Influenza virus infection may be complicated with bacterial infections or may be confused with influenza-like symptoms. In case of bacterial infection or suspected to be bacterial infection, appropriate measures should be taken, such as administration of anti-bacterial agents.
  • Favipiravir should be administered with care while co-administering with drugs that are contraindicated with favipiravir.
  • Increase of plasma level of favipiravir has been reported in patients with liver function impairment in a clinical safety and pharmacokinetic study conducted outside of Japan.
  • In animal studies, histopathological changes of test rats (12 weeks old) and young dogs (7 to 8 months old), and abnormal findings of sperm in mice (11weeks old) have been reported. Recovery or tendency of recovery has been observed in those studies after the administration was suspended.

Use in the elderly
Since the elderly often have reduced physiological functions, favipiravir should be administered with care to them by monitoring their general conditions under doctors discretion.

Use during Pregnancy, Delivery or Lactation
Do not administer Favipiravir to women known or suspected to be pregnant. (Early embryonic deaths [rats] and teratogenicity [monkeys, mice, rats and rabbits] have been observed in animal studies with exposure levels similar to or lower than the clinical exposure). When administering favipiravir to lactating women, instruct to stop lactating (The major metabolite of favipiravir, a hydroxylated form, was found to be distributed in breast milk).

Pediatric use
Favipiravir has not been administered to children. In a month study with juvenile dogs [8 weeks old], death cases have been reported after day 20 with a dosage [60 mg / kg / day] which was lower than the lethal dosage for young dogs [7 to 8 months old]. In juvenile animals [6-day-old rats and 8-week-old dogs], abnormal gait, atrophy and vacuolation of skeletal muscular fiber, degeneration / necrosis / mineralization of papillary muscle.

Potential drug-drug interactions

  • Favipiravir is not metabolized by cytochrome P-450 (CYP), mostly metabolized by aldehyde oxidase (AO), and partly metabolized by xanthine oxidase (XO). The drug inhibits AO and CYP2C8, but does not induce CYP.
  • Favipiravir inhibited irreversibly AO in a dose and time dependent manner, and inhibited CYP2C8 in a dose dependent manner. There was no inhibitory activity to XO, and weak inhibitory activity to CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. The hydroxylated metabolite showed weak inhibitory activity to CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Inductive effect of favipiravir on CYP was not observed.

Favipiravir should be used with caution with the following drugs

Drugs Associated risk
Pyrazinamide Blood uric acid level increases
Repaglinide Blood level of repaglinide may increase and adverse reactions to repaglinide may occur
Theophylline Blood levels of favipiravir may increase and adverse reactions to favipiravir may occur
Famciclovir, sulindac Efficacy of these drugs may be reduced

Adverse Reactions

Favipiravir has never been administered with the approved dosage. In clinical studies and the global phase III study (studies conducted with dose levels lower than the approved dosage), adverse reactions were observed in 100 of 501 subjects (19.96%) evaluated for the safety (including abnormal laboratory test values). Major adverse reactions included increase of blood uric acid level in 24 subjects (4.79%), diarrhoea in 24 subjects (4.79%), decrease of neutrophil count in 9 subjects (1.80%), increase of AST (GOT) in 9 subjects (1.80%), increase of ALT (GPT) in 8 subjects (1.60%).

Clinically significant adverse reactions
The following clinically significant adverse reactions have been reported with other similar anti-influenza virus agents, such as, shock, anaphylaxis, pneumonia, hepatitis fulminant, hepatic dysfunction, jaundice, toxic epidermal necrolysis (TEN), oculomucocutaneous syndrome (Stevens-Johnson syndrome), acute kidney injury, white blood cell count decreased, neutrophil count decreased, platelet count decreased, neurological and psychiatric symptoms (consciousness disturbed, abnormal behavior, deliria, hallucination, delusion, convulsion, etc.) and colitis haemorrhagic.
Patients should be carefully monitored, and if any abnormality is observed, the treatment should be discontinued and appropriate measures should be taken.

Other adverse reactions
If the following adverse reactions occur, appropriate measures should be taken according to the symptoms.

≥ 1% 0.5 - < 1% < 0.5%
Hypersensitivity Rash Eczema, pruritus
Hepatic AST (GOT) increased, ALT (GPT) increased, γ-GTP increased Blood ALP increased, blood bilirubin increased
Gastrointestinal Diarrhoea (4.79%) Nausea, vomiting, Abdominal pain Abdominal discomfort, duodenal ulcer, haematochezia, gastritis
Hematologic Neutrophil count decreased, white blood cell count decreased White blood cell count increased, reticulocyte count decreased, monocyte increased
Metabolic disorders Blood uric acid increased (4.79%), Blood triglycerides increased Glucose urine present Blood potassium decreased
Respiratory Asthma, oropharyngeal pain, rhinitis, nasopharyngitis
Others Blood CK (CPK) increased, blood urine present, tonsil polyp, pigmentation, dysgeusia, bruise, vision blurred, eye pain, vertigo, supraventricular extrasystoles

Reporting of suspected adverse reactions
Health care professionals, patients/consumers are advised to closely monitor the possibility of the above ADRs associated with the use of favipiravir. If such reactions are encountered, please report to the Hetero either by filling of Suspect Adverse Drug Reactions Reporting Form (form.heteroworld.com) or by Hetero Helpline No.1800-120-8689 and for all India safety cases and complaints, please write to drugsafetyindia@heterodrugs.com.

Pharmacology

It is considered that favipiravir is metabolized in cells to a ribosyl triphosphate form (favipiravir RTP) and that favipiravir RTP selectively inhibits RNA polymerase involved in influenza viral replication. With regards to the activity against human DNA polymerases α, β and γ, favipiravir RTP (1000 μmol/L) showed no inhibitory effect on α, 9.1-13.5% inhibitory effect on β and 11.7-41.2% inhibitory effect on γ. Inhibitory concentration (IC50) of favipiravir RTP on human RNA polymerase II was 905 μmol/L.

No change of susceptibility of type A influenza viruses to favipiravir was observed after 30 passages in the presence of favipiravir, and no resistant viruses have been selected. In clinical studies including the global phase III study, information about emergence of favipiravir-resistant influenza viruses has not been obtained. A polymerases α, β and γ, favipiravir RTP (1000 μmol/L) showed no inhibitory

Pharmacokinetics

Blood Concentrations: The following table shows pharmacokinetic parameters of favipiravir after an oral administration in 8 healthy adults at 1600 mg twice daily for 1 day, then 600 mg twice daily for 4 days followed by 600 mg once daily for1 day (1600 mg / 600 mg BID).

Distribution Results in non-Japanese: When favipiravir was orally administered to 20 healthy adult male subjects at 1200 mg twice daily for 1 day followed by 800 mg twice daily for 4 days (1200 mg/800 mg BID), the geometric mean concentration of the drug in semen was 18.341 μg/mL on Day 3, and 0.053 μg/mL on the second day after the treatment. The semen levels became below the limit of quantification (0.02 μg/mL) in all subjects in 7 days after the end of the treatment. The mean ratio of the drug concentration in semen to that in plasma was 0.53 on Day 3 and 0.45 on the second day after the treatment.

Metabolism: Favipiravir was not metabolized by cytochrome P-450 (CYP), mostly metabolized by aldehyde oxidase (AO), and partly metabolized to a hydroxylated form by xanthine oxidase (XO). In studies using human liver microsomes, formation of the hydroxylate ranged from3.98 to 47.6 pmol / mg protein/min, with an inter-individual variation of AO activity by 12 times at maximum. A glucuronate conjugate was observed in human plasma and urine as a metabolite other than the hydroxylated form.

Excretion: Favipiravir was mainly excreted as a hydroxylated form into the urine, and little amount unchanged drug was observed. In an oral 7-day multiple dose study with 6 healthy adults, cumulative urinary excretion ratio of the unchanged drug and the hydroxylated form was 0.8% and 53.1%, respectively, during 48 hours after the last administration.

Clinical data

1# Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study

Aim:

  • Examined the effects of Favipiravir (FPV) versus Lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19.

Method:

  • FPV oral dose: Day 1 - 1600 mg twice daily, Days 2–14 - 600 mg twice daily plus interferon (IFN)-a by aerosol inhalation (5 million U twice daily)
  • LPV/RTV oral dose: Days 1–14: 400 mg/100 mg twice daily plus IFN-a by aerosol inhalation (5 million U twice daily) were included in the control arm.

Outcomes:

  • Changes in chest computed tomography (CT), viral clearance, and drug safety.

Results:

  • 35 patients enrolled in the FPV arm and the 45 patients in the control arm.
  • A shorter viral clearance time was found for the FPV arm versus the control arm [median (interquartile range, IQR), 4 (2.5–9) d versus 11 (8–13) d, P < 0.001].
  • The FPV arm also showed significant improvement in chest imaging compared with the control arm, with an improvement rate of 91.43% versus 62.22% (P = 0.004).

Chest CT changes in patients with COVID-19 after treatment

Chest CT changes COVID-19 patients (N=80)
FPV (N=35) LVP/RTV (N=45) P value
Day 4 after treatment
Improve 8 (22.86%) 8 (17.78%) 0.42
Worse 9 (25.71%) 15 (33.33%)
Constant 18 (51.43%) 22 (48.89%)
Day 9 after treatment*
Improve 18 (56.25%) 16 (35.55%) 0.11
Worse 8 (25.00%) 16 (35.55%)
Constant 6 (18.75%) 13 (28.90%)
Day 14 after treatment
Improve 32 (91.43%) 28 (62.22%) 0.004
Worse 1 (3.23%) 9 (20.00%)
Constant 2 (6.45%) 8 (17.78%)

* For three patients in the FPV arm, the lung CT scan on Days 6-9 after medication was not carried out

  • Multivariable Cox regression showed that FPV was independently associated with faster viral clearance.

Time of viral shedding and improving chest CT scan on Day 14 after treatment

chest-CT-scan
  • Fewer adverse events were found in the FPV arm than in the control arm. Statistics of adverse reactions after medication
Characteristic Treatment
FPV (N=35) LPV/RTV (N=45) P value
Total number of adverse reactions 4 (11.43%) 25 (55.56%) < 0.001
Diarrhea 2 (5.71%) 5 (11.11%) 0.46
Vomiting 0 (0%) 5 (11.11%) 0.06
Nausea 0 (0%) 6 (13.33%) 0.03
Rash 0 (0%) 4 (8.89%) 0.13
Liver and kidney injury 1 (2.86%) 3 (6.67%) 0.63
Others 1 (2.86%) 2 (4.44%) 1.00

Conclusion

  • FPV showed better therapeutic responses on COVID-19 in terms of disease progression and viral clearance.
  • These preliminary clinical results provide useful information of treatments for SARS-CoV-2 infection.

2# Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial

Aim:

To analyse the clinical recovery rate of COVID-19 patients


Method:

  • Prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19.
  • Patients were randomly assigned in a 1:1 ratio to receive conventional therapy plus Umifenovir (200mg*3/day) or Favipiravir (1600mg*2/first day followed by 600mg*2/day) for 10 days.

Outcome:

  • Primary outcome: Clinical recovery rate of Day 7.
  • Secondary outcome: Latency to relief for pyrexia and cough, the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV).
  • Safety data were collected for 17 days.

Results:

  • 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive Favipiravir (116 assessed), and 120 to receive Umifenovir (120 assessed).
  • Clinical recovery rate of Day 7 was higher but not significant in Favipiravir group (71/116) and Umifenovir group (62/120) (P=0.1396).

Variables Favipiravir group Umifenovir group Rate ratio (95% CI) P value
Total patients (N=116) (N=120)
Recovered, n (%) 71 (61.21) 65 (51.67) 0.0954 (-0.0305, 0.2213) 0.1396
Moderate patients (N = 98) (N = 111)
Recovered, n (%) 70 (71.43) 62 (55.86) 0.1557 (0.0271, 0.2843) 0.0199
Severe or critical patients (N = 18) (N = 9)
Recovered, n (%) 1 (5.56) 0 (0.00) 0.0556 (-0.0503, 0.1614) 0.4712
Patients with hypertension and/or diabetes (N = 42) (N = 35)
Recovered, n (%) 23 (54.76) 18 (51.43) 0.0333 (-0.1904, 0.2571) 0.7704
clinical_recovry

  • Favipiravir led to shorter latencies to relief for both pyrexia (difference: 1.70 days, P < 0.0001) and cough (difference: 1.75 days, P < 0.0001).
Variables Time to relief for pyrexia Cough relief time
Favipiravir group Umifenovir group Favipiravir group Umifenovir group
Total patients (N = 71) (N = 74) (N = 78) (N = 73)
Day 1 15 (21.13) 2 (2.70) 1 (1.28) 3 (4.11)
Day 2 23 (32.39) 8 (10.81) 2 (2.56) 1 (1.37)
Day 3 19 (26.76) 18 (24.32) 23 (29.49) 7 (9.59)
Day 4 10 (14.08) 15 (20.27) 20 (25.64) 11 (15.07)
Day 5 1 (1.41) 16 (21.62) 10 (12.82) 12 (16.44)
Day 6 - 5 (6.76) 10 (12.82) 10 (13.70)
Day 7 - 3 (4.05) 3 (3.85) 3 (4.11)
Day 8 - - 7 (8.97) 6 (8.22)
Day 9 - - 1 (1.28) 3 (4.11)
Censored - - 1 (1.28) 17 (23.29)
Log-rank P value < 0.0001 < 0.0001

time_to_pyrexia
time_to_cough_relf

  • AOT or NMV rate was similar in both the groups (both P>0.05).

Other secondary outcomes
AOT or NMV* Favipiravir group Umifenovir group Rate ratio (95% CI) P value
Total patients N = 116 N = 120
With auxiliary, n (%) 21 (18.10) 27 (22.50) -0.0440 (-0.1464, -0.0585) 0.4015
Patients with hypertension and/or diabetes N = 42 N = 35
With auxiliary, n (%) 9 (21.43) 10 (28.57) -0.0714 (-0.2658, 0.1230) 0.4691
All-cause mortality 0 (0.00) 0 (0.00) / /
Dyspnea after taking medicine, n (%) 4 (3.45) 14 (11.67) / 0.0174
Respiratory failure, n (%) 1 (0.86) 4 (3.33) / 0.3700*

  • The most frequently observed Favipiravir-associated adverse event was raised serum uric acid (16/116, OR: 5.52, P=0.0014).

Comparison of antiviral-associated adverse effects.

Adverse effects Favipiravir group (N = 116) Umifenovir group (N = 120) P value
Frequency Cases, n (%) Frequency Cases, n (%)
Total 43 37 (31.90) 33 28 (23.33) 0.1410
Abnormal LFT 10 10 (8.62) 12 12 (10.00) 0.7156
Raised serum uric acid 16 16 (13.79) 3 3 (2.50) 0.0014
Psychiatric symptom reactions 5 5 (4.31) 1 1 (0.83) 0.1149 *
Digestive tract reactions 16 16 (13.79) 17 14 (11.67) 0.6239

*Fisher’s exact test was used for comparison between groups.

Conclusions:

  • Among patients with COVID-19, Favipiravir, compared to Umifenovir, did not significantly improve the clinically recovery rate at Day 7.
  • Favipiravir significantly improved the latency to relief for pyrexia and cough.
  • Adverse effects caused Favipiravir are mild and manageable.

3# A review of the safety of favipiravir – a potential treatment in the COVID-19 pandemic?

Aim:

To review existing favipiravir safety evidence, which is vital to informing the potential future use of favipiravir in COVI D-19.

Methods:

  • A search was conducted across EMBASE and MEDLINE databases, supplemented by relevant grey-literature and ClinicalTrials.gov.
  • All studies assessing the use of favipiravir in humans by 27 March 2020 were considered for inclusion. Further analysis of available safety data from phase 2 and 3 studies was undertaken.
  • Data extracted were adverse events (AEs) grade 1–4, serious AEs and discontinuation for AEs. Specific AEs of interest highlighted in early-phase studies, including gastrointestinal AEs and hyperuricaemia, were also examined.

Results:

  • Twenty-nine studies were identified as potential sources of evidence of the clinical safety of favipiravir. Six were phase 2 and 3 studies reporting relevant safety data for statistical comparison, representing a total of 4299 participants, an estimated 175 person-years-of-follow-up (PYFU).
  • Comparator drugs were oseltamivir, umifenovir, lopinavir/ritonavir or placebo. Study follow-up was between 5 and 21 days.
  • The proportions of grade 1–4 AEs on favipiravir was 28.2% vs 28.4% (P = n.s.) in the comparison arms.
  • The proportion of discontinuations due to AEs on favipiravir was 1.1% vs 1.2% (P = n.s.) in the comparison arms.
  • For serious AEs the proportion was 0.4% in both arms (P = n.s.).
  • There were significantly fewer gastrointestinal AEs occurring on favipiravir vs comparators [8.7% vs 11.5%; P = 0.003].
  • Favipiravir showed significantly more uric acid elevations than comparators [5.8% vs 1.3%; P < 0.0001].
Chen at al. Cai et al
Favipiravir Comparator Favipiravir Comparator
Grade 1-4 AE 37/116 (31.9) 28/120 (23.3) 4/35 (11.4) 25/45 (55.6)
GI AE 16/116 (13.8) 14/120 (11.7) 2/35 (5.7) 16/45 (35.6)
LFT elevations 9/116 (7.8) 12/120 (10.0) - -
Uric acid elevations 16/116 (13.8) 3/120 (2.5) - -

Conclusions:

  • Favipiravir demonstrates a favourable safety profile regarding total and serious AEs.
  • Safety concerns remain: hyperuricaemia, teratogenicity and QTc prolongation have not yet been adequately studied.
  • Favipiravir may be safe and tolerable in short-term use, but more evidence is needed to assess the longer-term effects of treatment.
  • Given the limitations of the evidence and unresolved safety concerns, caution is warranted in the widespread use of favipiravir against pandemic COVID-19.

Reference:

  • Pilkington V, Pepperrell T, et al. A review of the safety of favipiravir – a potential treatment in the COVID-19 pandemic? Journal of Virus Eradication 2020; 6: 45–51
  • Furuta Y, Gowen B, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013 November; 100(2). doi:10.1016/j.antiviral.2013.09.015.
  • Du YX and Chen XP. Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection. Received March 2, 2020; accepted April 2, 2020. doi:10.1002/cpt.1844
  • Cai Q, Yang M, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study, Engineering. https://doi.org/10.1016/j.eng.2020.03.007
  • Chen C, Zhang Y, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. Ahead of printing
  • https://www.europeanpharmaceuticalreview.com/news/116981/production-of-avigan-tablet-favipiravir-accelerated-for-use-against-covid-19/ (accessed on: 18/06/2020)
  • AVIGAN Prescribing information. (accessed on 18/06/2020)
  • FAVIVIR prescribing information (accessed on: 28/07/2020)

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References

FAVIVIR, Packaging Information (accessed on: 29/07/2020)

https://www.prnewswire.com/ae/news-releases/rdif-and-chemrar-launch-final-stage-of-favipiravir-clinical-trial-301064181.html (accessed on: 22/05/2020)