Gropivirin

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

Composition:

Active substance: inosine pranobex;

1 ml of syrup contains 50 mg of inosine pranobex;

Excipients: sucrose; sodium citrate monobasic anhydrous; methylparahydroxybenzoate (E 218); propylparahydroxybenzoate (E 216); sodium hydroxide; cherry flavoring; 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) deficiency or dysfunction of cellular immunity by inducing maturation and differentiation of T-lymphocytes and Th1-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 the level of immunoglobulin G as well as additional complement surface markers. Inosine pranobex enhances synthesis of interleukin-1 (IL-1) and interleukin-2 (IL-2), and regulates expression of IL-2 receptors. Inosine pranobex significantly increases secretion of endogenous gamma-interferon and reduces production of interleukin-4 in the body. Inosine pranobex enhances the activity of neutrophilic granulocytes, 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 by almost threefold.

Pharmacokinetics.

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

Distribution. When administered to animals, radiolabeled material was detected in the following organs (in order of decreasing specific activity): kidneys, lungs, liver, heart, spleen, testes, pancreas, brain, and skeletal muscles.

Metabolism. After oral administration in humans, plasma levels of radiolabeled inosine pranobex (1 g) showed the following concentrations of 1-dimethylamino-2-propanol and 4-acetylamidobenzoic acid: 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 increase in uric acid concentration—as an indicator of inosine metabolism—was found to be nonlinear and could vary within 10% over 1–3 hours.

Elimination. Daily urinary excretion of 4-acetylamidobenzoic acid and its main metabolite at steady state with daily administration of 4 g of the drug was approximately 85% of the administered dose. 95% of radioactivity of 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-acetylamidobenzoic acid. The main metabolites of inosine pranobex in humans are N-oxide for 1-dimethylamino-2-propanol and ortho-acylglucuronide for 4-acetylamidobenzoic 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-acetylamidobenzoic acid and its metabolite at steady state 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-acetylamidobenzoic 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, and 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 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 be administered with caution when used concomitantly with xanthine oxidase inhibitors or agents promoting uric acid excretion, including diuretic agents, 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, since concomitant use of immunosuppressants may affect its expected therapeutic effect due to peculiarities of 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® transient increases in serum and urinary uric acid levels may occur, particularly in men and elderly patients; however, these values usually remain within normal limits (up to 8 mg/dL or 420 µmol/L, respectively).

The increase in uric acid levels is due to the catabolic metabolism of inosine in humans. This phenomenon does not result from a fundamental drug-induced alteration in enzymatic function or renal clearance. Therefore, Groprivirin® should be used with particular caution in patients with gout, hyperuricemia, urolithiasis, or impaired renal function. Serum and urinary uric acid levels should be monitored throughout treatment in these 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, serum and urinary uric acid levels, liver function, blood parameters, and renal function should be monitored regularly in all patients.

Excipients of the medicinal product

The medicinal product Groprivirin®, syrup, contains methyl parahydroxybenzoate and propyl parahydroxybenzoate, 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 should not take this medicinal product.

Use during pregnancy or breastfeeding.

Controlled studies on fetal outcomes and fertility impairment in humans are lacking. It is unknown whether inosine pranobex is excreted in human breast milk. Therefore, during pregnancy and lactation, the drug should be administered only if the physician considers the expected benefit to outweigh the potential risk.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product Groprivirin® has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of administration and dosage.

The medication is intended for oral use.

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 administered throughout the day.

Adults, including elderly patients: the recommended daily dose is 50 mg/kg body weight (1 ml/kg), usually 3 g/day (20 ml of syrup 3–4 times daily). The maximum daily dose for adults is 80 ml of syrup (4 g of inosine pranobex).

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

*To measure the dose, a dosing device with a graduated scale, which is included 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 a 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. At the initial stage, 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 as needed, depending on the patient's condition and according to the physician's recommendation.

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

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

conditions with moderately severe symptoms – take for 60 days with a 30-day break;

conditions with severe symptoms – take for 90 days with a 30-day break.

The treatment course should be repeated as many times as necessary, with continuous monitoring of the patient's condition and indications for prolonged therapy.

In infections caused by human papillomavirus (external genital warts (condyloma acuminata) or papillomavirus infection of the cervical canal), 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 patients (patients without immunodeficiency or patients with low risk of recurrence), the drug is administered continuously for 14–28 days over a period of 3 months, followed by a two-month treatment-free period during which lesions decrease or disappear;

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

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

• genital papillomavirus infection lasting more than 2 years or with 3 or more recurrences in history;
• immunodeficiency caused by:
  • recurrent or chronic infections;
  • sexually transmitted diseases;
  • anticancer chemotherapy;
  • chronic alcoholism;
• poorly controlled diabetes mellitus;
• atopy (hereditary predisposition to hypersensitivity);
• prolonged use of contraceptives (longer than 2 years);
• erythrocyte folate levels ≤ 660 nmol/L;
• multiple sexual partners or change of regular sexual partner;
• frequent vaginal intercourse (≥ 2–6 times per week);
• anal intercourse;
• history of childhood skin warts;
• age > 20 years;
• chronic smoking.

In subacute sclerosing panencephalitis, the daily dose is 100 mg/kg body weight, with a maximum dose of 3-4 g/day. Treatment is long-term and continuous, with regular monitoring of the patient's health status and periodic reassessment of further therapy. The recommended daily dose may be increased, especially in severe cases.

Children.

The medicinal product Groprivirin®, syrup, is indicated for children from 1 year of age.

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 consistent adverse reaction observed during treatment with inosine pranobex in adults and children is a transient increase in serum and urinary uric acid levels, which return to baseline normal values within a few 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); very rare (≥ 1/10,000); frequency not known (cannot be estimated due to lack of data).

Immune system disorders: frequency not known – hypersensitivity reactions, anaphylactic reactions;

Ear and labyrinth disorders: common – vertigo;

Psychiatric disorders: uncommon – nervousness, insomnia;

Nervous system disorders: common – headache, vertigo; uncommon – somnolence; frequency not known – dizziness;

Gastrointestinal disorders: common – vomiting, nausea, epigastric discomfort; uncommon – diarrhea, constipation; frequency not known – upper abdominal pain;

Skin and subcutaneous tissue disorders: common – pruritus, skin rashes; frequency not known – erythema, angioneurotic edema, urticaria;

Musculoskeletal and connective tissue disorders: common – arthralgia;

Renal and urinary disorders: uncommon – polyuria;

General disorders: common – fatigue, malaise;

Investigations: very common – increased blood uric acid, increased urinary uric acid; common – increased transaminase levels, increased alkaline phosphatase levels in blood.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: 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 the reach and sight of children.

Packaging.

100 ml in a bottle. 1 bottle with an oral dosing syringe in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.