Avigan

INSTRUCTION for medical use of the medicinal product AVIGAN (AVIGAN)

Composition:

Active substance: favipiravir;

1 tablet contains 200 mg of favipiravir;

Excipients: colloidal anhydrous silicon dioxide, povidone (K30), low-substituted hydroxypropyl cellulose, crospovidone, sodium stearyl fumarate, hypromellose, titanium dioxide, talc, yellow iron oxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, light-yellow, film-coated tablets.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Other antiviral agents. Favipiravir.

ATC code J05AX27.

Pharmacological properties.

Pharmacodynamics.

Antiviral activity in vitro

The half-maximal effective concentration of favipiravir that reduces viral replication by 50% (EC₅₀) demonstrated activity against laboratory strains of influenza virus type A and type B, ranging from 0.014 to 0.55 µg/mL.

The EC₅₀ against seasonal influenza viruses of type A and type B, including strains resistant to adamantanes (amantadine and rimantadine), oseltamivir, or zanamivir, was 0.03–0.94 and 0.09–0.83 µg/mL, respectively.

The EC₅₀ against influenza viruses of type A and type B resistant to adamantanes, oseltamivir, and zanamivir was 0.09–0.47 µg/mL, with no observed cross-resistance.

The EC₅₀ against influenza viruses of type A (including strains resistant to adamantanes, oseltamivir, or zanamivir), such as swine influenza A and avian influenza A, including highly pathogenic strains (e.g., H5N1 and H7N9), ranged from 0.06 to 3.53 µg/mL.

Mechanism of action

Favipiravir is believed to be metabolized within cells to its ribofuranosyl triphosphate form (favipiravir RTP). Favipiravir RTP selectively inhibits RNA-dependent RNA polymerase, which is involved in influenza virus replication. Favipiravir RTP showed differential activity against human DNA polymerases α, β, and γ: at a concentration of 1000 µmol/L, favipiravir RTP did not inhibit α-polymerase, inhibited β-polymerase by 9.1–13.5%, and γ-polymerase by 11.7–41.2%. The inhibitory concentration (IC₅₀) of favipiravir RTP against human RNA polymerase II was 905 µmol/L.

Resistance

No changes in sensitivity of influenza virus type A to favipiravir were observed, and no resistant viruses were detected. In clinical studies, including a phase III international trial, there has been no evidence of emergence of favipiravir-resistant influenza viruses.

Pharmacokinetics.

Absorption

Plasma concentration

The pharmacokinetic parameters of favipiravir administered orally to 8 healthy adults at a dose of 1600 mg twice daily on Day 1, followed by 600 mg twice daily for 4 days and a single 600 mg dose on Day 6, are presented in the table below (Table 1).

Table 1

Pharmacokinetic parameters of favipiravir

Changes in the average plasma concentration of favipiravir (mean ± standard deviation)

After multiple oral doses of favipiravir administered to a healthy volunteer with low aldehyde oxidase (AO) activity over 7 days, the calculated AUC value of unchanged drug was 1,452.73 μg•h/mL on Day 1 and 1,324.09 μg•h/mL on Day 7.

Distribution

When 20 healthy adult males received oral favipiravir at a dose of 1,200 mg twice daily on Day 1, followed by 800 mg twice daily for 4 days, the geometric mean concentration of the drug in semen was 18.341 μg/mL on Day 3 of treatment and 0.053 μg/mL on Day 2 after discontinuation of the drug. Seven days after stopping the drug, its levels in semen were below the lower limit of quantification (0.02 μg/mL) in all study participants. The mean ratio of drug concentration in semen to its plasma concentration was 0.53 on Day 3 of treatment and 0.45 on Day 2 after discontinuation. The plasma protein binding rate was 53.4–54.4% (in vitro, centrifugal ultrafiltration method) at blood concentrations of 0.3–30 μg/mL.

Metabolism

Favipiravir is not metabolized by cytochrome P450 (CYP) isoenzymes. It is primarily metabolized by aldehyde oxidase (AO) and partially by xanthine oxidase (XO) to its hydroxylated form. In studies using human liver microsomes, hydroxylate formation ranged from 3.98 to 47.6 pmol/mg protein/min, with inter-individual variability in AO activity differing by up to 12-fold. A glucuronide conjugate was observed in human plasma and urine as a metabolite distinct from the hydroxylated form.

Excretion

Favipiravir is primarily excreted in the hydroxylated form in urine, with a small amount excreted unchanged. In a 7-day multiple oral dose study involving 6 healthy adults, the cumulative urinary excretion of the drug in unchanged and hydroxylated forms was 0.8% and 53.1%, respectively, within 48 hours after the last dose.

During a pharmacokinetic study conducted outside Japan, increased plasma levels of favipiravir were reported in patients with impaired liver function.

Clinical characteristics.

Indications.

For the treatment of new or recurrent pandemic influenza infections caused by the influenza virus, in cases where treatment with other antiviral agents has been ineffective or insufficiently effective.

Contraindications.

• Pregnancy or suspicion of pregnancy: embryonic death at an early stage and teratogenic effects were observed in animal studies (see sections "Special precautions" and "Use during pregnancy or breastfeeding");
• Hypersensitivity reactions to any component of the drug in medical history.

Interaction with other medicinal products and other types of interactions.

Favipiravir is not metabolized by cytochrome P450 (CYP) isoenzymes; it is metabolized primarily by aldehyde oxidase (AO) and partially by xanthine oxidase (XO). This drug inhibits AO and CYP2C8, but does not induce CYP isoenzymes (see section "Pharmacokinetics").

Precautions regarding concomitant use with other medicinal products

Table 2

Medicinal products with which favipiravir should be used with caution when administered concomitantly

In vitro, favipiravir irreversibly inhibited AO in a dose- and time-dependent manner and inhibited CYP2C8 in a dose-dependent manner. There was no inhibitory activity against XO and weak inhibitory activity against CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. The hydroxylated metabolite showed weak inhibitory activity against CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4.

Inductive effects of favipiravir on CYP enzymes were not observed.

Table 3

Effect of concomitant medicinal products on the pharmacokinetics of favipiravir

Table 4

Effect of favipiravir on the pharmacokinetics of concomitant medicinal products

Special precautions for use.

Warnings

1. Since embryonic death at early developmental stages and teratogenic effects have been observed in animal studies, Avigan must not be administered to women with confirmed or suspected pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
2. Before initiating treatment with Avigan in women of childbearing potential, a negative pregnancy test must be confirmed. Women must be thoroughly informed about the risks associated with use of this drug and strongly advised to use the most effective contraceptive methods both by the woman and her partner during treatment with this drug and for 7 days after its discontinuation (see section "Use during pregnancy or breastfeeding"). If pregnancy is suspected during treatment, the woman should be advised to immediately discontinue taking this drug and consult a physician.
3. Avigan penetrates into semen. When administering the drug to male patients, they must be thoroughly informed about the risks associated with treatment with this drug and strongly advised to use the most effective contraceptive methods during sexual intercourse throughout the treatment period and for 7 days after its completion (men must use condoms). Additionally, male patients must be informed that they should not have sexual contact with pregnant women (see sections "Use during pregnancy or breastfeeding" and "Pharmacokinetics").
4. Before initiating treatment, detailed information about the drug's efficacy and risks (including the risk of fetal effects) must be provided.
5. The necessity of using Avigan must be carefully considered before initiating treatment.

Precautions

1. Avigan is a drug that should only be considered during outbreaks of new or re-emerging influenza virus infections when other antiviral agents are ineffective or insufficiently effective. When treating with this drug, the most up-to-date information should be consulted, and the drug should be prescribed only to appropriate patients.
2. Avigan is not effective against bacterial infections.
3. Avigan is not intended for use in children (see section "Pediatric use").
4. Regardless of the route of administration or type of anti-influenza antiviral agents, cases of abnormal behavior have been reported in patients with influenza virus infection (see section "Adverse reactions"). To prevent accidents such as falls due to unusual behavior, patients or their caregivers should be instructed as a preventive measure that:
   • abnormal behavior may occur,
   • when patients are treated at home, caregivers or other individuals should take preventive measures against accidents such as falls for at least 2 days after the onset of fever. Severe forms of abnormal behavior leading to accidents such as falls have been more frequently observed in school-aged boys and minors. It is known that such symptoms are more likely to appear within 2 days after the onset of fever.

Patients should be closely monitored, and if any abnormalities are observed, treatment should be discontinued and appropriate measures taken.

1. Influenza virus infection may be complicated by bacterial infections or accompanied by symptoms that may be easily confused with influenza-like symptoms. In case of bacterial infection or suspected bacterial infection, appropriate measures such as administration of antibacterial agents should be taken.
2. Avigan contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Avigan is contraindicated in women with known or suspected pregnancy. In animal studies with exposure levels similar to or lower than clinical exposure, early embryonic death (in rats) and teratogenic effects (in monkeys, mice, rats, and rabbits) were observed.

Breastfeeding

Women who are breastfeeding should discontinue breastfeeding during treatment with Avigan. Studies have shown that the main metabolite of favipiravir, the hydroxylated form, penetrates into breast milk.

Since embryonic death at early developmental stages and teratogenic effects have been observed in animal studies, Avigan must not be administered to women with confirmed or suspected pregnancy (see section "Contraindications").

Before initiating treatment with Avigan in women of childbearing potential, a negative pregnancy test must be confirmed. Women must be thoroughly informed about the risks associated with use of this drug and strongly advised to use the most effective contraceptive methods both by the woman and her partner during treatment with this drug and for 7 days after its discontinuation. If pregnancy is suspected during treatment, the woman should be advised to immediately discontinue taking this drug and consult a physician.

Avigan penetrates into semen. When administering the drug to male patients, they must be thoroughly informed about the risks associated with treatment with this drug and strongly advised to use the most effective contraceptive methods during sexual intercourse throughout the treatment period and for 7 days after its completion (men must use condoms). Additionally, male patients must be informed that they should not have sexual contact with pregnant women for 7 days after the end of treatment (see section "Pharmacokinetics").

Effect on the ability to drive or operate machinery.

There are no data on the effect of favipiravir on the ability to drive vehicles or operate machinery.

Dosage and Administration

Treatment with this medicinal product should be initiated immediately upon the onset of influenza-like symptoms.

The total treatment duration is 5 days. The usual dose of Avigan for adults is 1600 mg (8 tablets) orally twice daily on the first day of treatment, followed by 600 mg (3 tablets) orally twice daily for the next 4 days.

Special Patient Populations

Elderly patients (> 65 years of age)

Since physiological functions are often reduced in elderly patients, Avigan should be administered with caution, with close monitoring of the patient's overall condition.

Pediatric patients (< 18 years of age)

This medicinal product is not intended for use in children.

Hepatic impairment

In patients with mild and moderate hepatic impairment (Child-Pugh classes A and B, 6 patients in each class), administration of Avigan orally at a dose of 1200 mg twice daily on the first day, followed by 800 mg twice daily for 4 days, resulted in Cmax and AUC values on day 5 being approximately 1.6 and 1.7 times higher, respectively, in patients with mild hepatic impairment, and 1.4 and 1.8 times higher in patients with moderate hepatic impairment, compared to healthy adult volunteers.

In patients with severe hepatic impairment (Child-Pugh class C, 4 patients), administration of Avigan orally at a dose of 800 mg twice daily on the first day, followed by 400 mg twice daily for 2 days, resulted in Cmax and AUC values on day 3 being approximately 2.1 and 6.3 times higher, respectively, compared to healthy adult volunteers.

Situations Requiring Caution

Avigan should be administered with caution to patients with active gout or a history of gout, as well as to patients with hyperuricemia (as serum uric acid levels may increase, potentially exacerbating symptoms).

Children

This medicinal product is not intended for use in children.

Overdose

There are no data available on Avigan overdose.

Adverse reactions.

Adverse reactions in individuals who participated in the study of the drug for the treatment of influenza

In clinical trials conducted in Japan and in the international Phase III study (trials conducted at doses lower than the approved dose), adverse reactions were observed in 100 out of 501 participants (19.96%) in whom safety was evaluated (including laboratory test abnormalities).

The most common adverse reactions included increased blood uric acid levels in 24 individuals (4.79%), diarrhea in 24 individuals (4.79%), decreased neutrophil count in 9 individuals (1.80%), increased AST (aspartate aminotransferase) levels in 9 individuals (1.80%), and increased ALT (alanine aminotransferase) levels in 8 individuals (1.60%).

Clinically significant adverse reactions (with similar medicinal products)

The following clinically significant adverse reactions have been reported with the use of other anti-influenza medicinal products. Patients should be carefully monitored, and if any disorders occur, treatment should be discontinued and appropriate measures taken.

• Shock, anaphylaxis.
• Pneumonia.
• Fulminant hepatitis, hepatic dysfunction, jaundice.
• Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome.
• Acute kidney injury.
• Leukopenia, neutropenia, thrombocytopenia.
• Neurological and psychiatric symptoms (disturbances of consciousness, delirium, hallucinations, delusions, convulsions, etc.).
• Although a causal relationship has not been established, neuropsychiatric symptoms such as abnormal behavior have been reported after administration of anti-influenza virus drugs, including the medicinal product Avigan (see section "Special precautions for use").
• Hemorrhagic colitis.

Other adverse reactions

If any of the following adverse reactions occur, symptomatic treatment should be initiated.

Table 5

Shelf life.

5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Packaging.

10 tablets per blister, 10 blisters per aluminium foil pouch; 1 pouch per carton.

Prescription status.

Prescription only.

Manufacturer.

TOYAMA FACTOR FUJIFILM TOYAMA CHEMICAL CO., LTD.

Manufacturer's location and address of business operations.

4-1, Shimookui 2-Chome, Toyama City, Toyama, Japan.