CYFAVIR

CYFAVIR

FAVIPIRAVIR 

Favipiravir was discovered for antiviral activity against the influenza virus by chemical modification of a pyrazine analog in a pyrazine carboxamide derivative (6-fluoro-3-hydroxy-2-pyrazinecarboxamide). It was approved for medical use in 2014, for the treatment of the new or re-emerging pandemic influenza virus infections. Favipiravir has proven efficacy against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1), and A(H7N9) avian virus.

Favipiravir is a new and emerging option for treatment of Covid-19. It has recently got approval for use to treat mild to moderate Covid-19 infections.

Mechanism of Action

The mechanism of its actions is related to the selective inhibition of viral RNA-dependent RNA polymerase. The mechanism of action of favipiravir is novel compared to existing influenza antivirals that primarily prevent entry and exit of the virus from cells. The active favipiravir-RTP selectively inhibits RNA polymerase and prevents replication of the viral genome.  Some studies have shown that when favipiravir-RTP is incorporated into a nascent RNA strand, it prevents RNA strand elongation and viral proliferation. It have also been found that the presence of purine analogs can reduce favipiravir’s antiviral activity, suggesting competition between favipiravir-RTP and purine nucleosides for RdRp binding.

Although favipiravir was originally developed to treat influenza, the RdRp catalytic domain (favipiravir’s primary target), is expected to be similar for other RNA viruses This conserved RdRp catalytic domain contributes to favipiravir’s broad-spectrum coverage.

Pharmacokinetics

Absorption-

The bioavailability of favipiravir is almost complete at 97.6%. The mean Cmax for the recommended dosing schedule of favipiravir is 51.5 ug/mL.

 Volume of distribution

The apparent volume of distribution of favipiravir is 15 – 20 L.

Protein binding

Favipiravir is 54% plasma protein-bound. Of this fraction, 65% is bound to serum albumin and 6.5% is bound to ɑ1-acid glycoprotein.

Metabolism

Favipiravir is extensively metabolized with metabolites excreted mainly in the urine. The antiviral undergoes hydroxylation primarily by aldehyde oxidase and to a lesser extent by xanthine oxidase to the inactive metabolite, T705M1.

Route of elimination

Favipiravir’s metabolites are predominantly renally cleared. 

Indications

Favipiravir is indicated for novel or re-emerging influenza virus infections (limited to cases in which other anti-influenza virus agents are not effective or insufficiently effective). It has also been approved for treatment of mild to moderate Covid-19 cases.

Side effects

Favipiravir may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • Shock
  • Anaphylaxis
  • Pneumonia
  • Hepatitis fulminant
  • Hepatic dysfunction
  • Jaundice
  • Toxic epidermal necrolysis
  • Oculomucocutaneous syndrome (Stevens-Johnson syndrome)
  • Acute kidney injury
  • Neurological and psychiatric symptoms (consciousness disturbed, abnormal behavior, deliria, hallucination, delusion, convulsion)
  • Colitis haemorrhagic.

 Drug- Drug Interactions

Precaution are to be used while administrating favipiravir with below mentioned drugs.

  • Pyrazinamide : Blood uric acid level increases
  • Repaglinide: Blood level of Repaglinide may increase causing hypoglycemia.
  • Theophylline : Blood level of Favipiravir may increase, and adverse reactions to Favipiravir may occur
  • Famciclovir , Sulindac : Efficacy of these drugs may be reduced

Warnings and Precautions

  • The administration should be started promptly after the onset of influenza-like symptoms.
  • Favipiravir should be administered with care in the following patients-:

Patients with gout or a history of gout, and patients with hyperuricaemia (blood uric acid level may increase, and symptoms may be aggravated).

  • Increased plasma level of favipiravir has been reported in patients with liver function impairment.
  • Psychoneurotic symptoms such as abnormal behaviour 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 behaviour such as fall, patients/their family should be instructed that, after the start of treatment with anti-influenza virus agents, (i) abnormal behaviour may be developed, and (ii) 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.
  • 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.
  • Patients should inform their doctors about any history of: Neurological abnormalities
    significant hypoxia or serious hepatic or electrolyte abnormalities or renal impairment.

Dose and Administration

  • For Mild to moderate COVID-19 (Under restricted emergency use in India) – The recommended dose of Favipiravir for adults (>18 years) is loading dose of 3,600 mg (1,800 mg BID) on day 1, followed by 1,600 mg per day (800 mg BID) From day 2 up to maximum of day 14.
  • For Novel/ emerging Influenza Infection – The usual dosage of Favipiravir for adults is 1600 mg orally twice daily for 1 day followed by 600 mg orally twice daily for 4 days. The total administration period should be 5 days.

Half-life

The elimination half-life of favipiravir is estimated to range from 2 to 5.5 hours.

Adverse Effects

Favipiravir is a well-tolerated drug with well-established safety profile. Favipiravir demonstrates a lower proportion adverse events, gastrointestinal adverse events, serious adverse events. The most frequent adverse effects reported in clinical trials were increased serum uric acid level, diarrhoea, decrease of neutrophil count, raised liver transaminases (AST, ALT) etc.

Storage
Store in a cool (below 30°C) and dry place protected from light. Keep away from the reach of children.

Over dosage-

There is limited clinical experience with favipiravir overdose in humans. Symptoms of overdose appear to include but are not limited to reduced body weight, vomiting, and decreased locomotor activity.

Contraindications

Favipiravir is contraindicated in patients who are hypersensitive to the active substance favipiravir or to any of the excipients, severe renal or hepatic impairment, women known or suspected to be pregnant, and lactating women.