Fapravir

Approved Indications:

• Influenza (Uncomplicated and Pandemic Strains):
  Used in Japan for treatment of novel or re-emerging influenza virus infections (including resistant strains) when other antivirals are ineffective.

Emergency and Clinically Accepted Off-Label Uses:

• COVID-19 (Mild to Moderate):
  Used in several countries under emergency use authorization (EUA) or compassionate use programs for the treatment of mild to moderate COVID-19, especially during early viral replication phase.
• Ebola Virus Disease (Experimental Use):
  Investigated as an experimental agent for Ebola virus infections.
• Lassa Fever, Nipah Virus, and Other Viral Hemorrhagic Fevers (Under Study):
  Used experimentally in selected viral infections where no specific antiviral exists.

Adults (COVID-19):

• Loading Dose: 1600 mg orally twice daily on Day 1
• Maintenance Dose: 600 mg orally twice daily from Day 2 to Day 10
• Duration: Typically 5 to 10 days depending on clinical response

Adults (Influenza):

• Loading Dose: 1600 mg orally twice daily on Day 1
• Maintenance Dose: 600 mg orally twice daily on Days 2–5

Elderly:

• No specific dose adjustment required unless renal or hepatic impairment is present. Monitor closely.

Renal Impairment:

• Use with caution in moderate to severe renal impairment. Limited data available. Dose adjustment may be required.

Hepatic Impairment:

• Use is not recommended in severe hepatic dysfunction due to risk of accumulation and toxicity.

Pediatrics:

• Not recommended due to lack of safety and efficacy data in children.

Administration:

• Oral administration with or without food. Swallow whole with water. Do not crush or chew.

Favipiravir is a prodrug that is converted intracellularly to its active form, favipiravir ribofuranosyl-5'-triphosphate (favipiravir-RTP). This active metabolite inhibits viral RNA-dependent RNA polymerase (RdRp), a crucial enzyme for viral replication. By acting as a purine analog, favipiravir-RTP gets incorporated into the viral RNA, leading to premature chain termination or lethal mutagenesis, thereby halting viral replication and reducing viral load. It does not affect host DNA or RNA polymerases at therapeutic doses.

• Absorption:
  Rapidly absorbed after oral administration with peak plasma levels (Tmax) within 2 hours.
• Bioavailability:
  Approximately 94% orally bioavailable.
• Distribution:
  Widely distributed with a volume of distribution (Vd) around 15–20 L. Penetrates lung tissues effectively.
• Protein Binding:
  Moderate, ~54%.
• Metabolism:
  Primarily metabolized by aldehyde oxidase and partly by xanthine oxidase in the liver to inactive hydroxylated metabolites.
• Half-life (t½):
  Approximately 2 to 5 hours in single doses; can increase with multiple dosing due to nonlinear kinetics.
• Excretion:
  Mainly via urine as inactive metabolites (>90%). Minimal fecal elimination.

• Pregnancy:
  Category X (Contraindicated):
  Teratogenic and embryotoxic in animal studies. Use is strictly contraindicated in pregnant women or women likely to become pregnant. Adequate contraception must be used during and after treatment.
• Lactation:
  Favipiravir is excreted in breast milk in animals. Due to potential adverse effects on the nursing infant, breastfeeding should be discontinued during treatment.

• Primary Class: Antiviral Agent
• Subclass: RNA Polymerase Inhibitor
• Type: Broad-Spectrum Antiviral Agent (Purine Nucleic Acid Analog)

• Known hypersensitivity to favipiravir or any of its components
• Pregnancy or suspected pregnancy
• Severe hepatic impairment
• Concurrent use with drugs that inhibit aldehyde oxidase (e.g., cimetidine) without proper monitoring
• Gout or hyperuricemia (due to uric acid elevation)

• Pregnancy and Teratogenic Risk:
  Strong teratogen. Contraindicated in pregnant women. Require negative pregnancy test and effective contraception during and for at least 7 days after therapy.
• Hepatic Impairment:
  Use with caution. Monitor liver enzymes regularly during therapy.
• Hyperuricemia:
  Favipiravir inhibits uric acid excretion, which can lead to elevated serum uric acid levels. Monitor in patients with gout or renal issues.
• QT Prolongation:
  Use with caution in patients with pre-existing QT prolongation or those taking QT-prolonging drugs.
• Pediatric Use:
  Safety and efficacy not established in patients under 18 years.
• Monitoring:
  Regular liver function tests, serum uric acid levels, and ECGs in at-risk patients.

Common Adverse Effects:

• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain
• Metabolic: Elevated uric acid (hyperuricemia)
• Hepatic: Elevated ALT, AST, and other liver enzymes
• Neurological: Dizziness, headache
• Psychiatric: Insomnia (less common)

Serious Adverse Effects:

• Liver injury or hepatitis (rare but severe)
• QT interval prolongation and arrhythmias
• Hypersensitivity reactions, including rash or anaphylaxis (rare)

Rare Effects:

• Blood dyscrasias (e.g., neutropenia)
• Visual disturbances (very rare, dose-related)

• Aldehyde Oxidase Inhibitors (e.g., cimetidine):
  May increase plasma favipiravir levels; monitor closely.
• Xanthine Oxidase Substrates (e.g., theophylline):
  Potential for increased plasma levels of these drugs.
• Drugs That Prolong QT (e.g., amiodarone, fluoroquinolones):
  May increase risk of torsades de pointes when co-administered.
• Alcohol:
  Use caution; may increase hepatic toxicity and reduce metabolism.
• No significant CYP450 interaction:
  Favipiravir is not a major substrate or inducer/inhibitor of CYP enzymes, reducing potential for classic CYP450 interactions.

• COVID-19 Use in 2021–2024:
  Several countries have revised or withdrawn emergency use authorizations due to limited evidence of clinical benefit, especially in moderate to severe disease stages.
• WHO Guidelines:
  Does not recommend favipiravir for routine COVID-19 treatment outside clinical trials due to inconsistent results.
• New Safety Monitoring:
  Enhanced pharmacovigilance required in regions where favipiravir is still in use, especially regarding liver injury and pregnancy risk.

• Storage Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Humidity: Store in a dry place; avoid high humidity.
• Light Protection: Keep in original container to protect from light.
• Handling:
• Keep out of reach of children.
• Handle with gloves if tablet is crushed or broken (due to teratogenic risk).
• No refrigeration required.
• Do not use past expiration date.