Gropivirin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GROPIVIRIN® (GROPIVIRIN)

Composition:

Active substance: inosine pranobex;

1 ml of syrup contains 100 mg of inosine pranobex;

Excipients: sucrose, sodium citrate monobasic anhydrous; methylparahydroxybenzoate (E 218); propylparahydroxybenzoate (E 216); sodium hydroxide; cherry flavor; purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: clear liquid, colorless to light brown, with a cherry odor.

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A X05.

Pharmacological Properties

Pharmacodynamics

Groprinosin® is an antiviral agent with immunomodulatory properties. The drug normalizes (to individual norm) the deficiency or dysfunction of cellular immunity by inducing maturation and differentiation of T-lymphocytes and T1-helper cells, and by enhancing the induction of lymphoproliferative response in mitogen- or antigen-activated cells.

Inosine pranobex modulates cytotoxic activity of T-lymphocytes and natural killer cells, regulates CD8 and CD4 function, and increases immunoglobulin G levels as well as complement surface markers. Inos游戏副本 pranobex enhances synthesis of interleukin-1 (IL-1) and interleukin-2 (IL-2), while regulating expression of IL-2 receptors. Inosine pranobex significantly increases secretion of endogenous gamma-interferon and reduces production of interleukin-4 in the body. It enhances the activity of neutrophilic granulocytes, and promotes chemotaxis and phagocytosis by monocytes and macrophages. Inosine pranobex inhibits viral replication by incorporating inosine-orotic acid into polyribosomes of virus-infected cells, inhibiting adenylic acid attachment to viral mRNA, and through molecular reorganization of lymphocytic intramembrane plasma particles, increasing their density nearly threefold.

Pharmacokinetics

Absorption. After oral administration, inosine pranobex is rapidly and completely absorbed (≥ 90%) from the gastrointestinal tract into the bloodstream.

Distribution. In animal studies using radiolabeled material, the compound and its components were detected in the following organs (in descending order of specific activity): kidneys, lungs, liver, heart, spleen, testes, pancreas, brain, and skeletal muscles.

Metabolism. Following oral administration in humans, plasma levels of 1-dimethylamino-2-propanol and 4-acetylaminobenzoic acid from 1 g of radiolabeled inosine pranobex were found to be 3.7 µg/mL (at 2 hours) and 9.4 µg/mL (at 1 hour), respectively. In known clinical dose-tolerance studies, peak post-dose elevation of uric acid concentration—used as an indicator of inosine metabolism—was found to be nonlinear and varied within 10% between 1–3 hours.

Excretion. Daily urinary excretion of 4-acetylaminobenzoic acid and its main metabolite at steady-state conditions with daily administration of 4 g of the drug amounted to approximately 85% of the administered dose. 95% of radioactively labeled 1-dimethylamino-2-propanol in urine was excreted as unchanged 1-dimethylamino-2-propanol and its metabolite (N-oxide). The elimination half-life is 3.5 hours for 1-dimethylamino-2-propanol and 50 minutes for 4-acetylaminobenzoic acid. The main metabolites of inosine pranobex in humans are N-oxide for 1-dimethylamino-2-propanol and ortho-acylglucuronide for 4-acetylaminobenzoic acid. Since inosine is metabolized via purine degradation to uric acid, radiolabeled inosine pranobex studies in humans are not informative. In animals, up to 70% of administered inosine pranobex may be excreted in urine as uric acid after oral administration of the tablet form, with the remainder excreted as usual metabolites—xanthine and hypoxanthine.

Bioavailability. Urinary determination of 4-acetamidobenzoic acid and its metabolite at steady-state conditions accounted for > 90% of expected values from solution. Determination of 1-dimethylamino-2-propanol and its metabolite accounted for > 76%. Plasma AUC values for 1-dimethylamino-2-propanol were ≥ 88%, and for 4-acetamidobenzoic acid – ≥ 77%.

Preclinical Safety Data

In various studies of acute, subacute, and chronic toxicity in mice, rats, dogs, cats, and monkeys, inosine pranobex demonstrated a low toxicity profile at doses up to 1500 mg/kg/day. The lowest acute lethal dose after oral administration was 50 times higher than the maximum recommended human therapeutic dose (100 mg/kg/day).

Long-term toxicological studies in mice and rats did not reveal any signs of carcinogenic potential.

Standard mutagenicity tests, in vivo studies in mice and rats, and in vitro studies in human peripheral blood lymphocytes showed no adverse effects.

There is no evidence of perinatal toxicity, embryotoxicity, teratogenicity, or impairment of reproductive function, as demonstrated in studies in mice, rats, and rabbits receiving continuous parenteral doses 20 times higher than the maximum recommended human therapeutic dose (100 mg/kg/day).

Clinical characteristics.

Indications.

• Viral respiratory infections;
• viral infections caused by herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, measles virus, mumps virus, including in patients with immunodeficiency states;
• papillomavirus infections of the skin and mucous membranes: anogenital warts, papillomavirus infection of the vulva, vagina, and cervix (as part of combination therapy);
• acute viral encephalitis (as part of combination therapy);
• viral hepatitis (as part of combination therapy);
• subacute sclerosing panencephalitis (as part of combination therapy).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product, acute gout, hyperuricemia.

Interaction with other medicinal products and other forms of interaction.

The medicinal product should not be taken simultaneously with immunosuppressants. Caution is advised when prescribing the medicinal product with xanthine oxidase inhibitors or agents promoting uric acid excretion, including diuretics, thiazide diuretics (such as hydrochlorothiazide, chlorthalidone, indapamide), or loop diuretics (such as furosemide, torasemide, ethacrynic acid).

Inosine pranobex should not be used during immunosuppressive therapy, as concomitant use of immunosuppressants may affect its expected therapeutic effect due to specific pharmacokinetic mechanisms (use is possible only after completion of immunosuppressive therapy).

When used concomitantly with zidovudine (azidothymidine), increased nucleotide formation occurs due to increased bioavailability of zidovudine in blood plasma and enhanced intracellular phosphorylation in human blood monocytes. This leads to potentiation of zidovudine effects under the influence of the medicinal product.

Special precautions for use.

During treatment with Groprivirin® drug, a temporary increase in serum and urinary uric acid levels may occur, especially in men and elderly patients; however, these parameters usually remain within normal limits (up to 8 mg/dL or 0.42 mmol/L, respectively).

The increase in uric acid levels is due to the catabolic metabolism of inosine in humans. This is not caused by a drug-induced fundamental alteration in enzyme function or renal clearance. Therefore, Groprivirin® should be used with particular caution in patients with gout, hyperuricemia, urolithiasis, and also in those with impaired renal function. During treatment, monitoring of uric acid levels is required in such patients.

In some patients, acute hypersensitivity reactions (angioneurotic edema, anaphylactic shock, urticaria) may occur. In such cases, treatment with Groprivirin® should be discontinued.

With prolonged use of the drug, there is a risk of developing nephrolithiasis.

During long-term therapy, regular monitoring of serum and urinary uric acid levels, liver function, blood parameters, and renal function should be performed in all patients.

Excipients of the drug.

The medicinal product Groprivirin®, syrup, contains methylparahydroxybenzoate and propylparahydroxybenzoate, which may cause allergic reactions (possibly delayed-type).

The medicinal product Groprivirin®, syrup, contains sucrose. Patients with rare hereditary disorders such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency must not take this medicinal product.

Each 1 mL of Groprivirin® syrup contains 0.65 g of sucrose. Use with caution in patients with diabetes mellitus.

Use during pregnancy or breastfeeding.

Controlled studies on fetal outcomes and fertility disturbances in humans are lacking. It is unknown whether inosine pranobex is excreted in human breast milk. Therefore, during pregnancy and breastfeeding, the drug should be prescribed only if the physician considers that the benefit outweighs the potential risk.

Ability to influence reaction rate while driving or operating machinery.

The medicinal product Groprivirin® does not affect the ability to drive a vehicle or operate machinery.

Method of administration and dosage.

The drug is administered orally.

The daily dose depends on body weight, course and severity of the disease, and patient's condition.

The daily dose should be evenly divided into doses taken throughout the day.

Adults, including elderly patients: the recommended daily dose is 50 mg/kg body weight (0.5 mL/kg), usually 3 g/day (10 mL of syrup 3–4 times daily). The maximum daily dose for adults is 40 mL of syrup (4 g of inosine pranobex).

Children from 1 year of age: the recommended daily dose is 50 mg/kg body weight (0.5 mL/kg), evenly divided into 3–4 doses according to the following table:

*To measure the dose, a dosing device with a measuring scale provided in the package should be used.

Duration of treatment.

Acute diseases. For diseases with a short course, the treatment duration is 5–14 days. After the symptoms subside, treatment should be continued for another 1–2 days or longer, depending on the course of the disease and the patient's condition.

Viral diseases with prolonged course. Treatment should be continued for 1–2 weeks after the symptoms subside, or longer, depending on the course of the disease and the patient's condition.

Recurrent diseases. During the initial stage of treatment, the same recommendations as for acute diseases should be followed. During maintenance therapy, the dose may be reduced to 500–1000 mg/day. At the first signs of recurrence, the daily dose recommended for acute diseases should be resumed and continued for 1–2 days after the symptoms disappear. The treatment course may be repeated several times if necessary, depending on the patient's condition and as advised by a physician.

Chronic diseases. The drug should be administered at a daily dose of 50 mg/kg body weight according to the following regimens:

asymptomatic diseases – take for 30 days with a 60-day break;

moderately symptomatic diseases – take for 60 days with a 30-day break;

severe symptomatic diseases – take for 90 days with a 30-day break.

The treatment course should be repeated as often as needed, with continuous monitoring of the patient's condition and indications for extending therapy.

In infections caused by human papillomavirus (external genital warts (condyloma acuminata) or cervical canal papillomavirus infection), administer 3 g/day for 14–28 days as monotherapy or as an adjunct to local therapy or surgical treatment according to the following regimens:

− for treatment of low-risk group patients (patients with normal immunity or low risk of recurrence): administer the drug continuously for 14–28 days, followed by a two-month treatment-free period during which lesions decrease or disappear, repeated over 3 months;

− for treatment of high-risk group patients* (patients with immunodeficiency or high risk of recurrence): administer the drug 5 days per week for 2 consecutive weeks each month, or 5 days per week every other week, over 3 months. If necessary, treatment courses may be repeated several times.

*Factors of high risk in patients with recurrences or cervical dysplasia, or genital papillomavirus infection, as in other similar diseases, include:

• immunodeficiency due to:
  • history of chronic or recurrent infections, or sexually transmitted diseases;
  • chemotherapy;
  • chronic alcoholism;
• prolonged use of oral contraceptives (over 2 years);
• erythrocyte folate levels below 660 nmol/L;
• multiple sexual partners or change of regular sexual partner;
• frequent vaginal intercourse (≥ 2–6 times per week) or anal sex;
• atopy (hereditary predisposition to hypersensitivity);
• poorly controlled diabetes;
• smoking;
• genital papillomavirus infection lasting more than 2 years or with 3 or more recurrences in history;
• negative history of skin warts in childhood.

In subacute sclerosing panencephalitis, the daily dose is 100 mg/kg body weight, with a maximum dose of 3–4 g/day, and continuous monitoring of the patient's condition and indications for continuing therapy is required. The recommended daily dose may be increased, especially in severe cases.

Children.

The medicinal product Groprivirin® syrup may be administered to children aged 1 year and older.

Overdose.

Cases of overdose have not been reported. Overdose may lead to increased levels of uric acid in blood serum and urine. Treatment is symptomatic.

Adverse Reactions

The only consistently observed adverse reaction during treatment with inosine pranobex in adults and children is a temporary increase in serum and urinary uric acid levels, which return to baseline normal values within several days after discontinuation of therapy.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated due to lack of data).

Very common. Laboratory investigations: increased blood uric acid, increased urinary uric acid.

Common. Laboratory investigations: increased transaminase levels, increased alkaline phosphatase levels in blood.

General disorders: increased fatigue, malaise.

Skin and subcutaneous tissue disorders: rash, pruritus.

Gastrointestinal disorders: vomiting, nausea, epigastric discomfort.

Nervous system disorders: headache, dizziness.

Musculoskeletal and connective tissue disorders: arthralgia.

Uncommon. Gastrointestinal disorders: diarrhea, constipation.

Nervous system disorders: somnolence.

Psychiatric disorders: nervousness, insomnia.

Renal and urinary disorders: polyuria.

During post-marketing surveillance of inosine pranobex, the following adverse reactions have been reported, for which frequency cannot be estimated due to insufficient data:

Gastrointestinal disorders: abdominal pain (upper abdomen);

Immune system disorders: anaphylactic reactions, hypersensitivity reactions;

Nervous system disorders: dizziness;

Skin and subcutaneous tissue disorders: erythema, Quincke's edema, urticaria.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Shelf life after first opening – 6 months.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 100 ml in a bottle. 1 bottle with dosing syringe in a cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of operations.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.