Areplivir^® Zinc (Tablets) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

ATC Code

J05AX (Other antiviral drugs)

Dosage Form

Areplivir® Zinc

Film-coated tablets, 200 mg+10 mg: 40 or 50 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light yellow to yellow in color, oval, biconvex; the core on the cross-section is white or white with a yellowish tint.

Excipients: microcrystalline cellulose – 108 mg, low-substituted hypromellose – 70 mg, povidone – 20 mg, crospovidone – 18 mg, colloidal silicon dioxide – 10 mg, sodium stearyl fumarate – 4 mg.

Film coating composition: hypromellose – 11.25 mg (62.5%), titanium dioxide (E171) – 5.416 mg (30.09%), macrogol (polyethylene glycol) – 1.125 mg (6.25%), yellow iron oxide dye (E172) – 0.209 mg (1.16%) or a ready-made film coating of identical composition – 18 mg.

10 pcs. – blister packs (4) – cardboard boxes.
10 pcs. – blister packs (5) – cardboard boxes.
40 pcs. – polymer jars (1) – cardboard boxes.
50 pcs. – polymer jars (1) – cardboard boxes.

Clinical-Pharmacological Group

Antiviral drug active against SARS-CoV-2 virus

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; other antiviral agents

Pharmacological Action

Combined antiviral agent.

Favipiravir inhibits the SARS-CoV-2 virus, which causes the new coronavirus infection (COVID-19). The EC₅₀ in Vero E6 cells is 61.88 µmol, which corresponds to 9.72 µg/ml. It has antiviral activity against laboratory strains of influenza A and B viruses (EC₅₀ 0.014-0.55 µg/ml). Favipiravir is metabolized in cells to favipiravir ribosyltriphosphate (favipiravir RTP) and selectively inhibits RNA-dependent RNA polymerase involved in influenza virus replication. Favipiravir RTP (1000 µmol/L) did not show an inhibitory effect on human αDNA, but showed an inhibitory effect in the range of 9.1 to 13.5% on β and in the range of 11.7 to 41.2% on human γDNA. The inhibitory concentration (IC₅₀) of favipiravir RTP for human RNA polymerase II was 905 µmol/L.

Zinc gluconate is a salt consisting of two molecules of gluconic acid for each zinc cation (Zn²⁺). Zinc is an essential trace element found in almost every cell of the human body. It is involved in numerous synthesis or degradation reactions of the most important metabolites (carbohydrates, lipids, proteins, as well as nucleic acids). Zinc is involved in the process of erythrocyte formation and other blood cells, plays an important role in the metabolism of RNA and DNA, and the metabolism of proteins and lipids. Zinc ions are involved in maintaining the activity of thymulin (thymus hormone), necessary for the maturation of T-helpers. Thus, Zinc plays an important role in the functioning of the T-cell immune system and ensuring an adequate response of the body’s immune system to the invasion of pathogenic microflora. Biological processes carried out with the participation of zinc-dependent proteins are important for regulating the biological activity of cytokines and for preventing a “cytokine storm”. Zinc is part of proteins involved in the body’s antiviral defense, including some involved in the recognition, processing, and degradation of single-stranded viral RNA. Zinc plays an important role in maintaining the protective properties of the pulmonary and intestinal epithelium – a biological barrier against the penetration of pathogenic microorganisms, has antioxidant properties – the ability to stabilize cell membranes and prevent their damage by free radicals formed during the inflammatory process.

Increased intracellular concentration of Zn²⁺ ions effectively disrupts the replication of RNA viruses (including nidoviruses, to which SARS-CoV-2 belongs) by inhibiting RdRp, the main enzyme involved in viral RNA replication, as well as by inhibiting cellular co-factors.

The zinc-dependent protein ZFP36 suppresses the synthesis of TNFα factor in interferon-induced macrophages, which ultimately leads to a reduction in virus-stimulated inflammatory reactions.

Favipiravir + Zinc. The use of the combination of favipiravir and zinc (in the form of zinc gluconate) leads to an expansion of the pharmacodynamic potential due to the wide range of effects of the formed coordination complex, which provides a direct antiviral and anti-inflammatory effect, supports the body’s protective properties, and increases the therapeutic efficacy of this combination.

Pharmacokinetics

After oral administration, Favipiravir is well absorbed from the gastrointestinal tract. T_max is 1.5 hours. With single intravenous administration of favipiravir in the dose range of 400-1800 mg, T_max ranges from 1.85 to 2.05 hours. Plasma protein binding is about 54%. When distributed in the human body, Favipiravir enters the semen. Favipiravir is mainly metabolized by aldehyde oxidase and partially metabolized to a hydroxylated form by xanthine oxidase. In cells, it is metabolized to favipiravir RTP. Among other metabolites, besides the hydroxylate, a glucuronate conjugate was also detected in human plasma and urine. It is excreted mainly by the kidneys as the active metabolite hydroxylate, a small amount is excreted unchanged. T_1/2 is about 5 hours.

Zinc is absorbed from the small intestine. Zinc absorption depends on its concentration in the intestinal lumen and increases linearly with increasing amounts of this trace element. After zinc enters the body with food, its level in the blood serum first increases and then decreases. The main carrier of zinc in blood plasma is albumin, with which about 60-70% of the zinc that enters the blood binds. The remaining 30-40% of zinc is transported by transferrin and alpha-2-macroglobulin. Any condition that changes the concentration of albumin in the blood serum can have a secondary effect on the serum zinc level. The main part of zinc ions in the blood is found in erythrocytes and leukocytes. The results of preclinical studies have shown that after entering the blood, zinc molecules are distributed to organs, including the liver, lungs, and kidneys within 72 hours.

In blood plasma, Zinc is metabolically active and responds to factors such as tissue damage and inflammation. During an inflammatory process, the zinc level in blood plasma decreases by up to 50%.

Zinc is released from food during its digestion in the form of free ions. Free ions can bind to endogenously secreted ligands before being transported into enterocytes in the duodenum and jejunum.

The portal system transports absorbed Zinc directly into the hepatic bloodstream, and then it is released into the systemic circulation for delivery to various tissues. Although serum Zinc accounts for only 0.1% of total body zinc, Zinc from blood plasma is rapidly taken up by organs and tissues and participates in cellular metabolism processes. Most zinc is excreted from the body through the gastrointestinal tract. A significant amount of zinc is secreted with bile, with most of the trace element being reabsorbed in the intestinal lumen. A smaller part of zinc is excreted in urine and sweat. In kidney disease, diabetes mellitus, and liver cirrhosis, increased excretion of zinc in the urine is observed.

Indications

Treatment of mild to moderate new coronavirus infection (COVID-19).

ICD codes

Dosage Regimen

Use this medication only under direct medical supervision in a hospital setting.

Take the tablets orally according to the following body weight-based regimen.

Initiate treatment immediately after laboratory confirmation of COVID-19 diagnosis or upon onset of characteristic clinical symptoms.

The total treatment course is 5 days.

For patients weighing 75 kg or more, take 1600 mg (8 tablets) twice daily on Day 1.

On Days 2 through 5, take 600 mg (3 tablets) twice daily.

For patients weighing less than 75 kg, take 1800 mg (9 tablets) as a single dose on Day 1.

On Days 2 through 5, take 800 mg (4 tablets) as a single daily dose.

Adhere strictly to the prescribed dosing schedule to maintain effective drug concentrations.

Do not exceed the total recommended dosage or duration of therapy.

If a dose is missed, take it as soon as you remember unless it is almost time for the next dose.

Do not double the dose to make up for a missed one.

Complete the full 5-day course even if symptoms improve earlier.

Adverse Reactions

Blood and lymphatic system disorders common – neutropenia, leukopenia; rare – leukocytosis, monocytosis, reticulocytopenia.

Metabolism and nutrition disorders common – hyperuricemia, hypertriglyceridemia; uncommon – glucosuria; rare – hypokalemia.

Immune system disorders uncommon – rash; rare – eczema, pruritus.

Respiratory, thoracic and mediastinal disorders rare – bronchial asthma, throat pain, rhinitis, nasopharyngitis.

Gastrointestinal disorders common – diarrhea; uncommon – nausea, vomiting, abdominal pain; rare – abdominal discomfort, duodenal ulcer, bloody stool, gastritis.

Hepatobiliary disorders common – increased ALT, AST, GGT activity; rare – increased ALP activity, increased blood bilirubin concentration.

Other rare – abnormal behavior, increased CPK activity, hematuria, laryngeal polyp, hyperpigmentation, taste disturbance, hematoma, blurred vision, eye pain, vertigo, supraventricular extrasystoles, chest pain.

Contraindications

Hypersensitivity to favipiravir, zinc gluconate; severe hepatic impairment (Child-Pugh class C); severe renal impairment and end-stage renal disease (GFR <30 ml/min); pregnancy, pregnancy planning, breastfeeding period; children under 18 years of age.

With caution

Patients with a history of gout and hyperuricemia (possible increase in uric acid levels and exacerbation of symptoms), elderly patients, patients with mild to moderate hepatic impairment (Child-Pugh class A and B), patients with moderate renal impairment (GFR <60 ml/min and ≥30 ml/min).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy, when planning pregnancy, and during breastfeeding.

When distributed in the human body, Favipiravir enters the semen.

It is necessary to use the most effective methods of contraception (condom with spermicide) during treatment with favipiravir and after its completion: for 1 month for women and for 3 months for men.

Additionally, it is necessary to instruct male patients not to engage in sexual contact with pregnant women.

If a possible pregnancy is suspected, it is necessary to immediately discontinue the use of this drug and consult a doctor.

If use during lactation is necessary, breastfeeding should be discontinued during treatment with favipiravir and for 7 days after its completion, because the main metabolite of favipiravir is excreted in breast milk.

Use in Hepatic Impairment

Contraindications: severe hepatic impairment (Child-Pugh class C).

With caution: patients with mild to moderate hepatic impairment (Child-Pugh class A and B).

Use in Renal Impairment

Contraindications: severe renal impairment and end-stage renal disease (GFR <30 ml/min).

With caution: patients with moderate renal impairment (GFR <60 ml/min and ≥30 ml/min).

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Use is possible only in a hospital setting.

During treatment, alcohol consumption should be avoided.

If adverse reactions occur, they must be reported in the established manner for pharmacovigilance measures.

Effect on ability to drive vehicles and operate machinery

Caution should be exercised when driving vehicles and operating machinery.

Drug Interactions

Favipiravir is not metabolized by cytochrome P450 system isoenzymes, it is mainly metabolized by aldehyde oxidase and partially metabolized by xanthine oxidase. It inhibits aldehyde oxidase and the CYP2C8 isoenzyme, but does not induce cytochrome P450 system isoenzymes.

When used concomitantly with pyrazinamide, hyperuricemia is observed due to an additional increase in uric acid reabsorption in the renal tubules.

When used concomitantly with repaglinide, an increase in the blood concentration of repaglinide is possible due to inhibition of the CYP2C8 isoenzyme and the development of adverse reactions associated with the action of repaglinide.

When used concomitantly with theophylline, an increase in the plasma concentration of favipiravir is possible due to interaction with xanthine oxidase, which may lead to an increase in the blood concentration of favipiravir and the development of adverse reactions to Favipiravir.

When used concomitantly with famciclovir, sulindac, a decrease in their efficacy is possible due to inhibition of aldehyde oxidase by favipiravir, which may lead to a decrease in the concentration of active forms of these substances in the blood.

Zinc salts reduce the absorption of tetracyclines, copper (the drug should be taken no earlier than 2 hours after taking these drugs).

Thiazide diuretics enhance the excretion of zinc by the kidneys.

Folic acid may slightly impair zinc absorption.

High doses of iron, penicillamine, and other complexing agents significantly reduce zinc absorption (should be taken no earlier than 2 hours after taking these drugs).

Complex preparations (e.g., multivitamin preparations with minerals containing Zinc) – simultaneous use of several preparations containing Zinc may lead to a high concentration of zinc in the plasma.

A diet rich in phosphates (e.g., dairy products), grain bakery products, or vegetables – limit zinc absorption by binding into non-absorbable complexes; such food can be consumed no less than 2 hours after taking zinc salts.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.