Coviflu

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT COVIFLU (COVIFLU)

Composition:

Active substance: favipiravir;

1 film-coated tablet contains 200 mg of favipiravir;

Excipients: L-hydroxypropylcellulose, crospovidone, colloidal silicon dioxide, povidone, sodium stearyl fumarate.

Film-coating composition: Opadry yellow 03A520072, hypromellose HPMC 2910 (E 464), talc, titanium dioxide (E 171), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Direct-acting antiviral agents. Other antiviral drugs. Favipiravir. ATC code J05AX27.

Pharmacological Properties

Pharmacodynamics

Antiviral activity in vitro

Favipiravir demonstrated antiviral activity against laboratory strains of influenza virus type A and type B, with EC₅₀ values ranging from 0.014 to 0.55 μg/mL.

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

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

The EC₅₀ against influenza viruses type A (including adamantane-, oseltamivir-, or zanamivir-resistant strains), such as swine influenza A and avian influenza A, including highly pathogenic strains (including 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 ribofuranosyltriphosphate form (favipiravir RTP). Favipiravir RTP selectively inhibits RNA-dependent RNA polymerase 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; it 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 have been observed, and no resistant viruses have been identified. Clinical studies, including a phase III international trial, have not reported emergence of resistance to favipiravir among influenza viruses.

Pharmacokinetics

Absorption

Plasma Concentration

The table below presents 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 (1600 mg/600 mg twice daily), then a single 600 mg dose once daily.

Table 1

Pharmacokinetic Parameters of Favipiravir

Changes in the mean 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 1452.73 μg·h/mL on Day 1 and 1324.09 μg·h/mL on Day 7.

Distribution

When 20 healthy adult males received oral favipiravir at a dose of 1200 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. Seven days after stopping the drug, semen levels were below the lower limit of quantification (0.02 μg/mL) in all study participants. The mean ratio of semen to plasma drug concentration was 0.53 on Day 3 of treatment and 0.45 on Day 2 after discontinuation. Plasma protein binding ranged from 53.4% to 54.4% (in vitro, using centrifugal ultrafiltration) 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 metabolized to its hydroxylated form by xanthine oxidase (XO). In studies using human liver microsomes, hydroxylate formation ranged from 3.98 to 47.6 pmol/mg protein/min, with up to a 12-fold difference in AO activity due to interindividual variability. A glucuronide conjugate has been observed in human plasma and urine as a metabolite distinct from the hydroxylated form.

Excretion

Favipiravir is excreted predominantly in the hydroxylated form in urine, with a small amount eliminated unchanged. In a 7-day multiple oral dose study in 6 healthy adults, the cumulative urinary excretion of unchanged and hydroxylated drug 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 early stages 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.

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

Precautions regarding concomitant use with other medicinal products

Table 2

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

In vitro, favipiravir irreversibly inhibited AO in a dose- and time-dependent manner and inhibited CYP2C8 in a dose-dependent manner. No inhibitory activity was observed toward CO, and weak inhibitory activity was observed 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 were not observed.

Table 3

Effect of concomitant medicinal products on the pharmacokinetics of favipiravir

Effect of favipiravir on the pharmacokinetics of concomitant medicinal products

Special precautions for use.

Warnings

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

Precautions

1. CoviFlu is a medication that should only be considered during outbreaks of new or re-emerging influenza virus infections when other antiviral agents are ineffective or insufficiently effective. Therapy with this drug should be based on up-to-date information and prescribed only to appropriate patients.
2. Favipiravir is not effective against bacterial infections.
3. Favipiravir is not intended for use in children (see section "Pediatric population").
4. Regardless of the route of administration or type of antiviral agent used against influenza, 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 accidental falls have been more frequently observed in school-aged boys and minors. It is known that such symptoms are more likely to occur 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 suspicion thereof, appropriate measures such as administration of antibacterial agents should be taken.

Use during pregnancy or breastfeeding

Pregnancy

CoviFlu is contraindicated in women with known or suspected pregnancy. In animal studies conducted at exposure levels similar to or lower than clinical exposure, embryo-fetal death at early stages (in rats) and teratogenic effects (in monkeys, mice, rats, and rabbits) were observed.

Breastfeeding

Women who are breastfeeding should discontinue breastfeeding while receiving CoviFlu. Studies have shown that the main metabolite of favipiravir—its hydroxylated form—passes into breast milk.

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

When administering favipiravir to women of reproductive age, a negative pregnancy test must be confirmed before initiating treatment. Women must be thoroughly informed about the risks associated with using this drug and strongly advised to use the most effective contraceptive methods both by the woman and her partner during treatment and for 7 days after discontinuation of the drug. If pregnancy is suspected during treatment, the woman should be advised to discontinue the drug immediately and consult her physician.

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

Ability to affect reaction speed when driving vehicles or operating machinery

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

Method of Administration and Dosage

Treatment with the drug should be initiated immediately upon the onset of influenza-like symptoms.

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

Special Patient Groups

Elderly patients (>65 years of age)

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

Pediatric patients (<18 years of age)

The 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), following oral administration of Coviflu at a dose of 1200 mg twice daily on the first day, followed by 800 mg twice daily for 4 days, Cmax and AUC values on day 5 were approximately 1.6 times and 1.7 times higher, respectively, in patients with mild hepatic impairment, and 1.4 times 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), following oral administration of favipiravir at a dose of 800 mg twice daily on the first day, followed by 400 mg twice daily for 2 days, Cmax and AUC values on day 3 were approximately 2.1 times and 6.3 times higher, respectively, compared to healthy adult volunteers.

Situations requiring cautious use

The medicinal product should be used with caution in patients with active gout or a history of gout, as well as in patients with hyperuricemia (in such patients, serum uric acid levels may increase, potentially exacerbating symptoms).

Children

The medicinal product is not intended for use in children.

Overdose

There is no available data on favipiravir overdose.

Adverse reactions.

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

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

The most common adverse reactions included elevated 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 elevated 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 should be 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 (disturbance 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 Coviflu (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.

2 years.

Storage conditions.

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

Keep out of reach of children.

Prescription status.

Prescription only.

Packaging.

Tablets, film-coated, 200 mg; 34 tablets in a blister pack, 1 blister pack in a cardboard box.

Manufacturer.

Glenmark Pharmaceuticals Ltd./Glenmark Pharmaceuticals Ltd.

Manufacturer's address.

Village Kishanpura, Baddi-Nalagarh Road, Tehsil Baddi, Distt. Solan (H.P.) 173 205, India.

Marketing Authorization Holder.

TLP Ukraine LLC.

Address of the Marketing Authorization Holder.

47, Mandrykovska Street, lit. M-2, corp. 2, premises 17, Zhovtnevyi district, Dnipro, Dnipropetrovsk region, 49094, Ukraine.