Inosine pranobex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INOSINE PRANOBEX (INOSINE PRANOBEX)

Composition:

Active substance: inosine pranobex;

1 ml of syrup contains inosine pranobex 50 mg;

Excipients: confectioner's sugar; methyl parahydroxybenzoate (E 218); propyl parahydroxybenzoate (E 216); citric acid monohydrate; sodium hydroxide; banana flavoring; purified water.

Pharmaceutical form. Syrup.

Main physico-chemical properties: syrup ranging from colorless to yellowish, with a banana odor and slightly bitter taste.

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

ATC code J05A X05.

Pharmacological Properties

Pharmacodynamics

The medicinal product INOSIN PRANOBEX contains methisoprinol (inosine pranobex), a synthetic purine derivative with immunomodulatory and antiviral activity resulting from pronounced stimulation of the host's immune response in vivo.

Clinical studies have demonstrated that inosine pranobex corrects deficiency or dysfunction of cellular immunity by inducing Th1-type immune responses, leading to maturation and differentiation of T-lymphocytes and potentiation of lymphoproliferative responses in mitogen- or antigen-activated cells. Furthermore, the drug has been shown to regulate cytotoxic mechanisms of T-lymphocytes and NK cells, function of CD8+ suppressor lymphocytes and CD4+ helper lymphocytes, as well as to increase IgG levels and surface complement markers. In vitro studies have shown that inosine pranobex enhances production of cytokines IL-1 and IL-2, while simultaneously increasing expression of the IL-2 receptor. In vivo studies demonstrated significantly increased secretion of endogenous gamma-interferon (IFN-γ) and reduced secretion of IL-4. The drug has also been shown to enhance chemotaxis and phagocytosis by neutrophils, monocytes, and macrophages.

In vivo studies have shown that inosine pranobex activates reduced synthesis of lymphocyte protein messenger RNA (mRNA) and enhances translation efficiency, while simultaneously inhibiting viral RNA synthesis through the following mechanisms (their involvement requires further investigation):

• incorporation of orotic acid bound to inosine into polyribosomes;
• inhibition of polyadenylic acid attachment to viral messenger RNA;
• restructuring of mesothelial protein complexes involved in signal transduction via the specific T-cell receptor (TcR) in lymphocyte intramembrane particles (IMP), increasing their density by almost threefold.

Inosine pranobex inhibits cGMP-phosphodiesterase in vitro only at high concentrations; this effect does not occur at drug concentrations that provide immunopharmacological activity in vivo.

Pharmacokinetics

Absorption. After oral administration, inosine pranobex is rapidly and completely absorbed (≥ 90%) from the gastrointestinal tract into the bloodstream. Similarly, 94–100% of the dose of its components, DIP (N,N-dimethylamino-2-propanol) and PABA (para-aminobenzoic acid), administered intravenously, was recovered in urine after oral administration in rhesus macaques.

Distribution. In studies conducted in monkeys, radiolabeled material was detected in the following organs (in descending order of specific activity): kidneys, lungs, liver, heart, spleen, testes, pancreas, brain, and skeletal muscles.

Metabolism. After oral administration in humans, administration of 1 g of radiolabeled inosine pranobex revealed plasma concentrations of DIP and PABA at 3.7 µg/mL (at 2 hours) and 9.4 µg/mL (at 1 hour), respectively.

Dose tolerance studies have shown that peak post-dose elevation of uric acid concentration, as an indicator of methisoprinol metabolism, is nonlinear and may vary within ±10% over 1–3 hours.

Elimination. Daily urinary excretion of PABA and its main metabolite at steady state with a dosage of 4 g/day accounted for approximately 85% of the administered dose. 95% of radiolabeled DIP was recovered in urine as unchanged substance and its N-oxide metabolite. The elimination half-life of DIP is 3.5 hours and of PABA is 50 minutes. The main metabolites of inosine pranobex in humans are N-oxide for DIP and ortho-acylglucuronide for PABA. Since the inosine molecule is metabolized via purine biodegradation to uric acid, radiolabeled inosine pranobex studies in humans are non-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 recovery of PABA and its metabolite at steady state was > 90% of expected values from solution. Recovery of DIP and its metabolite was ≥ 76%. Plasma AUC values for DIP were ≥ 88% and for PABA ≥ 77%.

Clinical characteristics.

Indications.

The medicinal product INOZIN PRANOBEX 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 (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV);

• genital warts (condyloma acuminata) — external lesions (excluding meatal and perianal localization) — either as monotherapy or as an adjunct to conventional local or surgical treatment;

• mucosal infections, subclinical vulvovaginal infections, or infections caused by HPV (human papillomavirus) associated with the endocervix;

• viral hepatitis;

• complicated measles or measles with complications;

• subacute sclerosing panencephalitis (SSPE).

Contraindications.

The medicinal product must not be used:

• in patients with known hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• in patients during an acute attack of gout;
• in patients with elevated blood uric acid levels (hyperuricemia).

Interaction with other medicinal products and other forms of interaction.

Use with caution in patients receiving xanthine oxidase inhibitors (e.g., allopurinol) and agents that enhance urinary excretion of uric acid, including thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone, indapamide) and loop diuretics (furosemide, torasemide, ethacrynic acid).

The medicinal product should not be taken 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).

Concomitant administration of the medicinal product with zidovudine (azidothymidine — AZT) enhances the formation of zidovudine nucleotides through different mechanisms resulting from increased zidovudine plasma bioavailability and increased intracellular phosphorylation in blood monocytes. This leads to potentiation of zidovudine effects under the influence of the drug.

Special precautions for use.

The medicinal product may cause a transient increase in serum and urinary uric acid levels, which usually remains within normal limits (upper limit being 8 mg/dL or 0.42 mmol/L, respectively), particularly in elderly individuals and younger males. The increase in uric acid levels results from the catabolic metabolism of the active substance's inosine component into uric acid and is not due to changes in enzyme activity or renal clearance caused by drug administration. Therefore, inosine pranobex should be used with caution in patients with a history of gout, hyperuricemia, urolithiasis, or impaired renal function. During treatment, careful 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 the medicinal product should be discontinued.

Renal calculi may form during prolonged therapy. In every patient undergoing long-term treatment, regular monitoring of serum and urinary uric acid levels, liver function, blood parameters, and renal function should be performed.

Excipients.

The medicinal product INOSINE PRANOBEX contains methylparahydroxybenzoate (E 218) and propylparahydroxybenzoate (E 216) and therefore may cause allergic reactions (possibly delayed).

The medicinal product contains confectionery sugar. If you have been diagnosed with intolerance to certain sugars, consult your physician before taking this medicinal product. It may be harmful to teeth. One ml of syrup contains 663 mg of confectionery sugar. Use with caution in patients with diabetes mellitus.

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

Use during pregnancy or breastfeeding.

The effects of inosine on fetal development and human fertility 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 unless the physician considers the expected benefit to outweigh the potential risks.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

The medicinal product is intended for oral administration.

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). Maximum daily dose — 4 g.

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

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

Duration of treatment

Acute diseases. For diseases with a short course, the treatment duration is 5 to 14 days. After reduction in the severity of disease symptoms, treatment should be continued for another 1–2 days or longer, as decided by the physician.

Viral diseases with prolonged course. Treatment should be continued for 1–2 weeks after reduction in the severity of disease symptoms or longer, as decided by the physician.

Recurrent diseases. At the beginning 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 symptom resolution. Treatment courses may be repeated several times as necessary and depending on the patient's condition, as recommended by the physician.

Chronic diseases. The recommended dose is 50 mg/kg body weight according to the following regimens:

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

mild symptomatic diseases: take for 60 days with a 30-day break;

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

Treatment courses should be repeated as often as needed, 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 involving the endocervix: 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 with low risk of recurrence), the drug is administered continuously for 14–28 days over 3 months, 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 recurrence), the medicinal product is administered 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.

*The "high-risk" profile for recurrence or cervical dysplasia in patients with genital HPV infection resembles that of other diseases and includes the following conditions and states:

• Genital HPV infection lasting more than 2 years, or history of 3 or more recurrences.
• Immunosuppression due to:
  • recurrent or chronic infections;
  • other sexually transmitted infections (STIs);
  • chemotherapy for oncological diseases;
  • chronic alcoholism.
• Poorly controlled diabetes.
• Atopy.
• Long-term use of oral contraceptives (2 years or more).
• Erythrocyte folate level below 660 nmol/L.
• Multiple sexual partners or change of regular sexual partner.
• Frequent vaginal intercourse (≥ 2–6 times per week).
• Anal sex.
• History of childhood cutaneous warts.
• Age over 20 years.
• Smoking.

In subacute sclerosing panencephalitis, the daily dose is 100 mg/kg body weight, maximum dose ― 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. See section "Method of administration and dosage."

Overdose.

Cases of overdose have not been reported. Based on toxicological studies in animals, serious adverse reactions are unlikely, except for increased uric acid levels in the body. Treatment is symptomatic and supportive.

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 presented according to the following classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Shelf life. 2 years.

The shelf life of the medicinal product after opening the bottle is no more than 12 months.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Do not store in the refrigerator.

Packaging.

100 ml or 150 ml in a bottle; 1 bottle with a dosing device in a pack.

Prescription status. Prescription only.

Manufacturer.

LLC "DKP "Pharmaceutical Factory".

Manufacturer's address and location of its business activity.

4, Korolova St., Stanishivka village, Zhytomyr district, Zhytomyr region, 12430, Ukraine.