Areplivir, 200 mg 40 pcs

Pharmacotherapeutic group: antiviral medicine

ATX code: J05AX27

Pharmacological properties

Pharmacodynamics

Antiviral activity in vitro

Favipiravir has antiviral activity against laboratory strains of influenza A and B viruses (half maximum effective concentration (EC₅₀) 0.014-0.55 µg/ml).

For influenza A and B virus strains resistant to adamantan (amantadine rimantadine), oseltamivir or zanamivir, the EC₅₀ is 0.03-0.94 µg/mL and 0.09-0.83 µg/mL, respectively. For influenza A virus strains (including strains resistant to adamantan, oseltamivir, and zanamivir) such as swine influenza type A and avian influenza type A, including highly pathogenic strains (including H5N1 and H7N9), the EU₅₀ is 0.06-3.53 µg/ml.

For influenza A and B virus strains resistant to adamantan, oseltamivir, and zanamivir, the EC₅₀ is 0.09-0.47 µg/mL; no cross-resistance is observed.

Favipiravir inhibits the SARS-CoV-2 virus that causes new coronavirus infection (COVID-19). The EC₅₀ in Vero E6 cells is 61.88 μmol, corresponding to 9.72 μg/mL.

Mechanism of Action

Favipiravir is metabolized in cells to favipiravir ribosyltriphosphate (favipiravir RTF) and selectively inhibits the RNA-dependent RNA polymerase involved in influenza virus replication. Favipiravir RtF (1000 μmol/L) showed no inhibitory effect on human α DNA, but showed inhibitory effects ranging from 9.1% to 13.5% on β and from 11.7% to 41.2% on human γ DNA. The inhibitory concentration (IC₅₀) of Favipiravir RTP for human RNA polymerase II was 905 μmol/L.

Resistance

After 30 transfections in the presence of favipiravir, no changes in the susceptibility of influenza A viruses to favipiravir were observed, and no resistant strains were observed either. No influenza viruses resistant to favipiravir have been observed in clinical studies.

Pharmacokinetics

Intake

Favipiravir is easily absorbed in the gastrointestinal tract. Time to reach maximum concentration (T_mah) 1.5 h.

Distribution

The binding to plasma proteins is about 54%.

Metabolism

Favipiravir is primarily metabolized by aldehydoxidase and partially metabolized to the hydroxylated form by xanthine oxidase. In cells the RTP of favipiravir is metabolized. Of the other metabolites, in addition to hydroxylate, glucuronate conjugate was also recorded in human plasma and urine.

Favipiravir is mainly excreted by the kidneys as the active metabolite hydroxylate, a small amount unchanged. The elimination half-life (T_1/2) is about 5 h.

Patients with impaired liver function

When favipiravirvir is taken by patients with mild to moderate hepatic impairment (Child-Pugh class A and B) increases C_max and AUC were 1.5-fold and 1.8-fold, respectively, compared with healthy volunteers. These increases in C_max and AUC for patients with severe hepatic impairment (Child-Pugh class C) were 2.1-fold and 6.3-fold, respectively.

Patients with renal impairment

In patients with moderate renal impairment (GFR < 60 ml/min and ≥30 ml/min) the residual concentration of favipiravir (Cthrough) was increased 1.5-fold compared to patients without renal impairment. In patients with severe and terminal renal impairment (FFR < 30 ml/min) the drug has not been studied.

Indications

Treatment of new coronavirus infection (COVID-19).

Pharmacological effect

Pharmacotherapeutic group: antiviral agent

ATX code: J05AX27

Pharmacological properties

Pharmacodynamics

Antiviral activity in vitro

Favipiravir has antiviral activity against laboratory strains of influenza A and B viruses (half maximum effective concentration (EC50) 0.014-0.55 μg/ml).

For strains of influenza A and B viruses resistant to adamantane (amantadine rimantadine), oseltamivir or zanamivir, the EC50 is 0.03-0.94 µg/ml and 0.09-0.83 µg/ml, respectively. For influenza A virus strains (including strains resistant to adamantane, oseltamivir and zanamivir), such as swine influenza type A and avian influenza type A, including highly pathogenic strains (including H5N1 and H7N9), the EC50 is 0.06-3.53 μg/ml.

For strains of influenza A and B viruses resistant to adamantane, oseltamivir and zanamivir, the EC50 is 0.09-0.47 μg/ml; cross-resistance is not observed.

Favipiravir inhibits the SARS-CoV-2 virus, which causes novel coronavirus disease (COVID-19). EC50
in Vero cells E6 is 61.88 µmol, which corresponds to 9.72 µg/ml.

Mechanism of action

Favipiravir is metabolized in cells to favipiravir ribosyl triphosphate (favipiravir RTP) and selectively inhibits RNA-dependent RNA polymerase involved in influenza virus replication. Favipiravir RTF (1000 μmol/L) showed no inhibitory effect on human α DNA, but showed an inhibitory effect ranging from 9.1 to 13.5% on β and ranging from 11.7 to 41.2% on human γ DNA. The inhibitory concentration (IC50) of favipiravir PTF for human RNA polymerase II was 905 μmol/L.

Resistance

After 30 subcultures in the presence of favipiravir, no changes were observed in the susceptibility of influenza A viruses to favipiravir, and no resistant strains were observed. Clinical studies have not revealed the emergence of influenza viruses resistant to favipiravir.

Pharmacokinetics

Suction

Favipiravir is easily absorbed from the gastrointestinal tract. Time to reach maximum concentration (Tmax) 1.5 hours.

Distribution

Plasma protein binding is about 54%.

Metabolism

Favipiravir is primarily metabolized by aldehyde oxidase and partially metabolized to its hydroxylated form by xanthine oxidase. Favipiravir RTF is metabolized in cells. Of the other metabolites, in addition to hydroxylate, glucuronate conjugate was also recorded in human blood plasma and urine.

Removal

Favipiravir is primarily excreted by the kidneys as the active hydroxylate metabolite, with a small amount unchanged. The half-life (T1/2) is about 5 hours.

Patients with liver dysfunction

When favipiravir was administered to patients with mild to moderate hepatic impairment (Child-Pugh class A and B), the increases in Cmax and AUC were 1.5-fold and 1.8-fold, respectively, compared to healthy volunteers. These increases in Cmax and AUC for patients with severe hepatic impairment (Child-Pugh class C) were 2.1 times and 6.3 times, respectively.

Patients with impaired renal function

In patients with moderate renal impairment (GFR <60 mL/min and ≥30 mL/min), the trough concentration of favipiravir (Cthrough) increased 1.5-fold compared to patients without renal impairment. The drug has not been studied in patients with severe and terminal renal failure (GFR < 30 ml/min).

Special instructions

If a side effect develops, it is necessary to report this in the prescribed manner for the implementation of pharmacovigilance activities.

Because fetal death and teratogenicity were observed in animal studies with favipiravir, AREPLIVIR should not be administered to pregnant or suspected pregnant women.

1) When prescribing AREPLIVIR to women capable of childbearing (including those less than 2 years postmenopausal), it is necessary to confirm a negative pregnancy test result before starting treatment. Women of childbearing potential should be fully explained the risks and carefully instructed to use the most effective method of contraception with their partners while taking the drug and for 1 month afterwards (condom with spermicide). If you suspect a possible pregnancy, you should immediately stop taking the drug and consult your doctor.

2) When distributed in the human body, favipiravir enters the sperm. When prescribing the drug to male patients, the risks should be fully explained and carefully instructed to use the most effective methods of contraception during sexual intercourse while taking the drug and for 3 months after its end (condom with spermicide). Additionally, male patients should be instructed not to have sexual contact with pregnant women.

3) When distributed in the human body, favipiravir passes into breast milk. When prescribing the drug, breastfeeding women should be fully explained the risks and carefully instructed to stop breastfeeding while taking the drug and for 7 days after it ends.

Impact on the ability to drive vehicles and machinery

Care should be taken when driving vehicles and operating machinery.

Active ingredient

Favipiravir

Composition

For 1 tablet:

Active ingredient:

Favipiravir – 200.0 mg

Excipients:

Povidone (K-30), colloidal silicon dioxide, low-substituted hyprolose, microcrystalline cellulose (type 101), crospovidone, stearic acid.

Film casing:

Ready-made film coating Opadry® 03F220114 yellow [Hypromellose, titanium dioxide, macrogol 4000 (Polyethylene glycol 4000), yellow iron oxide dye E172].

Contraindications

Hypersensitivity to favipiravir or any component of AREPLIVIR.

Severe liver failure (class C according to the Child-Pugh classification).

Renal failure of severe and terminal severity (GFR < 30 ml/min).

Pregnancy or planning pregnancy.

Breastfeeding period.

Children under 18 years of age.

With caution

In patients with gout and a history of hyperuricemia (possible increased levels of uric acid in the blood and exacerbation of symptoms), in elderly patients, patients with mild to moderate liver failure (Child-Pugh class A and B), patients with moderate renal failure (GFR < 60 ml/min and ≥ 30 ml/min).

Side Effects

In the clinical study of AREPLIVIR, the incidence of patients with reported adverse events was 24.04% (25/104). Increased alanine aminotransferase (ALT) activity was observed in 17.3% (18/104) of patients, increased aspartate aminotransferase (AST) activity in 12.5% ​​(13/104) and increased creatine phosphokinase activity in 0.9% (1/104) of patients. These adverse reactions are consistent with the known adverse drug reactions of favipiravir presented in Table 1.

The assessment of the incidence of adverse reactions is based on the WHO classification: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (< 1/10000); frequency is unknown (it is not possible to establish the frequency from the available data).

Table 1. Adverse reactions

Classification by organ systems

Adverse reactions

Blood and lymphatic system disorders

often: neutropenia, leukopenia

rare: leukocytosis, monocytosis, reticulocytopenia

Metabolic and nutritional disorders

often: hyperuricemia, hypertriglyceridemia

uncommon: glycosuria

rare: hypokalemia

Immune system disorders

uncommon: rash

rare: eczema, itching

Respiratory, thoracic and mediastinal disorders

rarely: bronchial asthma, sore throat, rhinitis, nasopharyngitis

Gastrointestinal disorders

often: diarrhea

uncommon: nausea, vomiting, abdominal pain

rare: abdominal discomfort, duodenal ulcer, bloody stools, gastritis

Disorders of the liver and biliary tract

often: increased ALT activity, increased AST activity, increased gamma-glutamyltransferase (GGT) activity

rarely: increased alkaline phosphatase (ALP) activity, increased bilirubin concentration in the blood

Other

rare: abnormal behavior, increased creatine phosphokinase (CPK) activity, hematuria, laryngeal polyp, hyperpigmentation, impaired taste sensitivity, hematoma, blurred vision, eye pain, vertigo, supraventricular extrasystoles, chest pain

Interaction

Favipiravir is not metabolized by cytochrome P450, mainly metabolized by aldehyde oxidase and partly by xanthine oxidase. Favipiravir inhibits aldehyde oxidase and cytochrome CYP2C8, but does not induce cytochrome P450.

Table 2. Drug-drug interactions

Medicines

Signs, symptoms and treatment

Mechanism of action and risk factors

Pyrazinamide

Hyperuricemia

Additionally, the reabsorption of uric acid in the renal tubules increases.

Repaglinide

The concentration of repaglinide in the blood may increase, and adverse reactions to repaglinide may develop.

Inhibition of CYP2C8 leads to increased blood concentrations of repaglinide.

Theophylline

The concentration of favipiravir in the blood may increase, and adverse reactions to favipiravir may develop

Interaction with xanthine oxidase may lead to increased concentrations of favipiravir in the blood.

Famciclovir,

sulindak

The effectiveness of these drugs may be reduced

Inhibition of aldehyde oxidase by favipiravir may lead to a decrease in the concentration of active forms of these drugs in the blood.

Overdose

There are no reports of overdose with favipiravir.

Storage conditions

At a temperature not exceeding 25 ºС in secondary packaging.

Keep out of the reach of children.

Shelf life

2 years.

Do not use after expiration date.

Manufacturer

Biokhimik JSC, Russia