INOPRANOL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INOPRANOL

Composition:

Active substance: inosine pranobex;

250 mg of inosine pranobex in 5 ml of syrup;

Excipients: sucrose (saccharose), methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), citric acid monohydrate, sodium hydroxide, plum flavor, purified water.

Medicinal form. Syrup.

Main physicochemical characteristics: clear, viscous liquid, colorless or slightly yellowish, with a specific odor.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antiviral agents for systemic use. Direct-acting antiviral agents. Other antiviral agents. Inosine pranobex.

ATC code J05A X05.

Pharmacological Properties

Pharmacodynamics

Inopranol is an antiviral agent with immunomodulatory properties. Inosine pranobex normalizes (to individual norm) deficiency or dysfunction of cellular immunity by inducing maturation and differentiation of T-lymphocytes and T1-helper cells, and by potentiating the lymphoproliferative response in mitogen-stimulated or antigen-activated cells.

Inosine pranobex modulates cytotoxic activity of T-lymphocytes and natural killer cells, function of CD8+ suppressor lymphocytes and CD4+ helper lymphocytes, and also increases the level of immunoglobulin G and complement surface markers. It enhances synthesis of interleukin-1 (IL-1) and interleukin-2 (IL-2), 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, chemotaxis, and phagocytosis by monocytes and macrophages. Inosine pranobex inhibits viral replication through the following potential mechanisms:

• incorporation of inosine orotic acid into polyribosomes of virus-infected cells;
• inhibition of adenylic acid attachment to viral mRNA;
• molecular reorganization of intramembranous lymphocyte 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. In animal studies with radiolabeled inosine pranobex, radioactivity was detected in the following organs (in descending order of concentration): kidneys, lungs, liver, heart, spleen, testes, pancreas, brain, and skeletal muscles.

Metabolism. After oral administration of 1 g of radiolabeled inosine pranobex to humans, plasma levels of 1-dimethylamino-2-propanol and 4-acetamidobenzoic acid reached 3.7 µg/mL (at 2 hours) and 9.4 µg/mL (at 1 hour), respectively. Clinical dose-tolerance studies have shown that peak increase in uric acid concentration, as an indicator of inosine metabolism, is nonlinear and may vary within 10% during 1–3 hours.

Elimination. Daily urinary excretion of 4-acetamidobenzoic acid and its main metabolite at steady state, following daily administration of 4 g of the drug, accounted for approximately 85% of the administered dose. 95% of the radioactive 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-acetamidobenzoic acid. The main metabolites of inosine pranobex in humans are the N-oxide of 1-dimethylamino-2-propanol and the ortho-acylglucuronide of 4-acetamidobenzoic 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 is 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 amounts of 4-acetamidobenzoic acid and its metabolite at steady state were > 90% of expected values from solution. Amounts of 1-dimethylamino-2-propanol and its metabolite were > 76%. Plasma AUC values for 1-dimethylamino-2-propanol were ≥ 88%, and for 4-acetamidobenzoic acid — ≥ 77%.

Clinical characteristics.

Indications. The medicinal product Inopranol is indicated for the treatment of reduced or dysfunctional cellular immunity and for the treatment of clinical symptoms associated with the following diseases:

• primary and secondary viral respiratory infections;
• viral infections caused by herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus;
• genital warts (Condyloma acuminata) — external lesions (excluding meatal (within the anal canal) and perianal localization) — as monotherapy or as an adjunct to conventional local or surgical treatment;
• skin and mucous membrane infections, vulvovaginal (subclinical) infections or infections caused by HPV (human papillomavirus) associated with the endocervix — as part of combination therapy;
• viral hepatitis — as part of combination therapy;
• complicated measles or measles with complications;
• 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.

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

The medicinal product Inopranol should be prescribed with caution when used concomitantly with xanthine oxidase inhibitors (e.g., allopurinol) or agents promoting uric acid excretion, including diuretics, thiazide diuretics (such as hydrochlorothiazide, chlorthalidone, indapamide), or loop diuretics (such as furosemide, torasemide, ethacrynic acid).

Concomitant use with zidovudine (azidothymidine) increases nucleotide formation 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 drug.

Special precautions for use

During treatment with Inopranol, a temporary increase 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 and 420 µmol/l, respectively).

The increase in uric acid levels results from the catabolic metabolism of the inosine component of the active substance into uric acid and is not due to changes in enzyme activity or renal clearance caused by drug administration. Therefore, the medicinal product should be used with particular caution in patients with a history of gout, hyperuricemia, urolithiasis, or impaired renal function. In such patients, serum uric acid levels should be monitored regularly during treatment.

Prolonged use of Inopranol carries a risk of developing nephrolithiasis. In all patients undergoing long-term treatment, monitoring of serum and urinary uric acid levels, liver function, blood parameters, and renal function should be performed.

Acute hypersensitivity reactions (angioneurotic edema, anaphylactic shock, urticaria) may occur in some patients. In such cases, Inopranol therapy should be discontinued.

Excipients. The medicinal product Inopranol contains methylparahydroxybenzoate and propylparahydroxybenzoate, which may cause allergic reactions (possibly of delayed type).

This medicinal product contains 6.5 g of sucrose in 10 ml; therefore, it should be used with caution in patients with diabetes mellitus. It may be harmful to teeth.

This medicinal product should not be administered to patients with rare hereditary disorders such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

10 ml of syrup contains 1 mmol of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding. The effects of inosine on fetal development and fertility in humans have not been studied. It is unknown whether inosine pranobex passes into breast milk. The medicinal product should not be used during pregnancy or breastfeeding.

Ability to influence reaction speed when driving or operating machinery. Inopranol has no effect or has a negligible effect on the ability to drive vehicles or operate machinery.

However, when making decisions about driving or operating machinery, it should be taken into account that the medicinal product may cause dizziness or other adverse reactions affecting the nervous system (see section "Adverse reactions").

Dosage and Administration.

The medicinal product should be administered orally.

The daily dose depends on body weight, course and severity of the disease, and the 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 (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 aged 1 year and older: the recommended daily dose is 50 mg/kg body weight (1 mL/kg), evenly divided into 3–4 doses according to the following table:

* The dosing device with a measuring scale supplied with the medicinal product should be used for dose measurement.

Duration of treatment

Acute diseases. For conditions with a short course, the treatment duration is 5–14 days. After alleviation of disease symptoms, 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 reduction in severity of symptoms 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. Upon appearance of the first signs of relapse, the daily dose recommended for acute diseases should be resumed and continued for 1–2 days after symptom disappearance. The treatment course may be repeated several times as needed, depending on the patient's condition and upon physician's recommendation.

Chronic diseases. The medicinal product 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 expressed 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.

Dosing for special indications

External genital condyloma (Condyloma acuminata) or HPV infections associated with the endocervix: administer 3 g/day for 14–28 days either 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 with low risk of relapse): the drug is administered continuously for 14–28 days followed by a two-month treatment-free period during which lesions decrease or disappear;

or

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

* Factors indicating high risk of recurrence or cervical dysplasia in patients with 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 level ≤ 660 nmol/L;
• multiple sexual partners or change of regular sexual partner;
• frequent vaginal intercourse (≥ 2–6 times per week);
• anal intercourse;
• history of skin warts in childhood;
• age > 20 years;
• chronic smoking.

In subacute sclerosing panencephalitis, the daily dose is 100 mg/kg body weight, with a maximum dose of 60–80 ml/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 can be used in 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 adverse effect of inosine pranobex that occurs most frequently in both adults and children is a temporary increase (usually within normal limits) in serum and urinary uric acid levels, which return to initial normal values within a few days after completion of treatment.

The frequency of adverse reactions is specified according to the following classification: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), frequency not known (cannot be estimated based on available data).

Reporting of adverse reactions following registration of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After first opening of the packaging, the shelf life is 6 months, provided the product is stored at a temperature not exceeding 25 °C.

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

Keep out of reach and sight of children.

Packaging. 120 mL of the preparation in a bottle, 1 bottle with a dosing device in a carton.

Prescription status. Prescription only.

Manufacturer. Public Joint Stock Company "Scientific and Production Center "Borshchahivskyy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of operations. 17 Myru Street, Kyiv, 03134, Ukraine.