Normomed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMOMED (NORMOMED)

Composition:

Active substance: inosine pranobex;

5.0 g of inosine pranobex in 100 ml of syrup;

Excipients: sucrose, glycerol, methylparahydroxybenzoate (E 218), propyl-parahydroxybenzoate (E 216), citrus fruit flavor, purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: clear, slightly yellowish liquid with a characteristic citrus flavor.

Pharmacotherapeutic group. Direct-acting antiviral agents.

ATC code J05AX05.

Pharmacological Properties.

Pharmacodynamics.

Isoprinosine (inosine pranobex) consists of two components: inosine – the active component, which is a purine metabolite, and the salt of 4-acetamidobenzoic acid with N,N-dimethylamino-2-propanol – an auxiliary component that enhances the availability of inosine to lymphocytes.

The active and auxiliary components are present in a molar ratio of 1 : 3.

The active substance, inosine pranobex, exerts direct antiviral and immunomodulatory effects. The direct antiviral effect is due to binding to ribosomes of virus-infected cells, which slows down the synthesis of viral messenger RNA (mRNA), leading to inhibition of replication of both RNA- and DNA-genome viruses; the indirect effect is explained by induction of interferon production.

In known in vivo studies, it was found that inosine pranobex activates reduced synthesis of lymphocyte protein mRNA and enhances translational efficiency, while simultaneously inhibiting viral RNA synthesis through the following mechanisms: incorporation of orotic acid bound to inosine into polyribosomes, inhibition of polyadenylic acid attachment to viral mRNA, and restructuring of intramembranous lymphocytic plasma particles (IMP), increasing their density by almost threefold.

The immunomodulatory effect is mediated through action on T-lymphocytes (activation of cytokine synthesis) and enhancement of macrophage phagocytic activity. Inosine pranobex promotes differentiation of pre-T-lymphocytes, stimulates mitogen-induced proliferation of T- and B-lymphocytes, increases functional activity of T-lymphocytes, including their ability to produce lymphokines, normalizes the ratio between the main regulatory subpopulations CD4+/CD8+, and promotes normalization of T-memory cell formation.

Inosine pranobex significantly enhances production of interleukin-2 (IL-2) by lymphocytes and promotes expression of receptors for this interleukin on lymphoid cells; it also stimulates natural killer (NK) cell activity, enhances macrophage activity in phagocytosis, antigen processing, and presentation, thereby increasing the number of antibody-producing cells in the body from the first days of treatment. Inosine pranobex also regulates cytotoxic mechanisms of T-lymphocytes and NK cells.

Inosine pranobex stimulates synthesis of interleukin-1 (IL-1), microbial killing activity, expression of membrane receptors, and the ability to respond to lymphokines and chemotactic factors.

In known in vivo studies, a significant increase in endogenous gamma-interferon (IFN-γ) production and a decrease in interleukin-4 (IL-4) production were observed.

In herpes virus infections, formation of specific anti-herpetic antibodies is significantly accelerated, and clinical symptoms as well as recurrence frequency are reduced.

Inosine pranobex prevents post-viral suppression of cellular RNA and protein synthesis in infected cells, which is particularly important for cells involved in immune defense mechanisms. As a result of this complex action, viral load on the body is reduced, immune system function is normalized, endogenous interferon synthesis is significantly activated, promoting resistance to infectious diseases and rapid localization of infection foci if they occur.

Pharmacokinetics.

Inosine pranobex has high bioavailability. After oral administration, it is rapidly absorbed; maximum plasma concentration of inosine is reached within 1 hour. After 2 hours, the concentration decreases to undetectable levels. The half-life is 50 minutes. Pharmacological effects appear approximately 30 minutes after administration and last up to 6 hours.

Inosine pranobex is rapidly metabolized and excreted by the kidneys.

Inosine is metabolized via the typical pathway for purine nucleosides, forming uric acid (the first metabolite), whose concentration in blood serum may occasionally increase. The second metabolite [1-(dimethylamino)-2-propanol-(4-acetamidobenzoate)] is excreted by the kidneys as glucuronides and partially in unchanged form.

No accumulation in the body has been observed. Complete elimination of metabolites occurs within 48 hours.

Clinical characteristics.

Indications.

• Viral infections in patients with normal and reduced immune status: influenza, parainfluenza, acute respiratory viral infections, viral bronchitis, rhinovirus and adenovirus infections; epidemic parotitis, measles (as part of complex therapy).
• Diseases caused by Herpes simplex virus type I or Herpes simplex type II (herpes labialis, facial skin, oral mucosa, skin of hands, ophthalmic herpes), subacute sclerosing panencephalitis, genital herpes; Varicella zoster virus (chickenpox and herpes zoster, including recurrent forms in immunodeficient patients); Epstein-Barr virus (infectious mononucleosis); cytomegalovirus; human papillomavirus; acute and chronic hepatitis B (as part of complex therapy).
• Chronic recurrent respiratory tract and urogenital system infections in patients with weakened immunity (including chlamydia and other diseases caused by intracellular pathogens) (as part of complex therapy).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Acute gout attack.
• Hyperuricemia.

Interaction with other medicinal products and other types of interactions.

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).

Normomed, syrup, should not be used concomitantly with immunosuppressants due to possible pharmacokinetic interaction that may affect the expected therapeutic effect. Concurrent use with zidovudine (azidothymidine) enhances the formation of zidovudine nucleotides through different mechanisms, leading to increased serum bioavailability of zidovudine and enhanced intracellular phosphorylation in monocytes. This results in potentiation of zidovudine effects under the influence of Normomed.

Special precautions for use.

It should be remembered that Normomed, like other antiviral agents, is most effective in acute viral infections when treatment is initiated at an early stage of the disease (preferably within the first 24 hours). The drug should be used as part of combination therapy with antibiotics and other etiotropic agents.

The active ingredient of the drug is metabolized to uric acid and may cause a significant increase in its concentration in urine. Therefore, Normomed should be used with caution in patients with a history of gout, hyperuricemia, urolithiasis, or renal insufficiency. When use in these patients is necessary, careful monitoring of uric acid concentration is required. During prolonged treatment (3 months or longer), monthly monitoring of serum and urinary uric acid concentrations, liver function, peripheral blood count, and renal function parameters is advisable.

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

Elderly patients. Dose adjustment is not required; the drug is administered at the adult dosage. In elderly patients, increased levels of uric acid in serum and urine are observed more frequently than in middle-aged individuals.

The syrup contains 13 g of sucrose per dose and should therefore be used with caution in patients with diabetes mellitus. The drug contains methyl parahydroxybenzoate (E 218) and propyl parahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed) and, in individual cases, bronchospasm.

Use during pregnancy or breastfeeding.

The medicinal product is not recommended during pregnancy or breastfeeding due to the lack of clinical studies on its use during these periods.

Ability to affect reaction speed when driving or operating machinery.

The effect of the drug on reaction speed during driving or operating machinery has not been studied. However, when deciding whether to drive or operate machinery, it should be taken into account that the drug may cause dizziness or other adverse reactions affecting the nervous system (see section "Adverse reactions").

Method of Administration and Dosage.

The drug is taken orally, preferably after meals, at regular intervals. The duration of treatment is determined individually depending on the nosology, severity of the condition, and frequency of relapses; on average, treatment lasts 5–14 days. If necessary, the course of treatment may be repeated after a 7–10-day break. Treatment with intervals and maintenance doses may last up to 1–6 months. Dosage is determined individually based on age, body weight, and severity of the condition.

Maximum daily dose for adults: 4 g of inosine pranobex, corresponding to 80 mL of syrup.

Recommended doses and administration regimens:

• Influenza, parainfluenza, acute respiratory viral infections:
  Adults – 20 mL of syrup 3–4 times daily;
  Children – daily dose calculated at 50 mg/kg (i.e., 1 mL syrup/kg body weight) divided into 3–4 doses for 5–7 days; if necessary, treatment may be prolonged or repeated after a 7–8-day interval. For maximum efficacy in acute respiratory viral infections, treatment should begin at the first signs of illness or from the first day of illness. The drug is usually continued for another 1–2 days after symptoms have resolved;

• Viral bronchitis:
  Adults – 20 mL of syrup 3 times daily;
  Children – daily dose calculated at 50 mg/kg (i.e., 1 mL syrup/kg) divided into 3–4 doses for 2–4 weeks;

• Epidemic parotitis (mumps): daily dose calculated at 70 mg/kg (i.e., 1.4 mL syrup/kg) divided into 3–4 doses for 7–10 days;

• Measles: daily dose calculated at 100 mg/kg (i.e., 2 mL syrup/kg) divided into 3–4 doses for 7–14 days;

• Aphthous stomatitis:
  Adults – 20 mL of syrup 4 times daily;
  Children – daily dose calculated at 70 mg/kg (i.e., 1.4 mL syrup/kg) divided into 3–4 doses for 6–8 days (acute phase); subsequently,
  Adults – 20 mL of syrup 3 times daily,
  Children – 50 mg/kg (i.e., 1 mL syrup/kg) divided into 3–4 doses twice weekly for 6 weeks;

• Infectious mononucleosis: daily dose calculated at 50 mg/kg (i.e., 1 mL syrup/kg) divided into 3–4 doses for 8 days;

• Cytomegalovirus infection: daily dose calculated at 50 mg/kg (i.e., 1 mL syrup/kg) divided into 3–4 doses for 25–30 days;

• Herpes zoster and labial herpes:
  Adults – 20 mL of syrup 3–4 times daily;
  Children – daily dose calculated at 50 mg/kg (i.e., 1 mL syrup/kg) divided into 3–4 doses for 10–14 days (until symptoms resolve);

• Genital herpes: during acute phase – 20 mL of syrup 3 times daily for 5–6 days; during remission, maintenance dose – 20 mL of syrup (1000 mg) once daily for up to 6 months;

• Subacute sclerosing panencephalitis: daily dose calculated at 50–100 mg/kg (i.e., 1–2 mL syrup/kg) divided into 6 doses (every 4 hours) for 8–10 days; after an 8-day break, 1–3 additional courses for mild cases, up to 9 courses for severe cases;

• Infections caused by Human papilloma virus (anogenital warts): 20 mL of syrup 3 times daily for 14–28 days, or in combination with cryotherapy or CO₂-laser therapy – 20 mL of syrup 3 times daily for 3 courses with 1-month intervals between courses;

• Hepatitis B:
  Adults – 20 mL of syrup 3–4 times daily for 15–30 days; subsequently, maintenance dose – 20 mL of syrup (1000 mg) once daily for 2–6 months;

• Chronic recurrent respiratory and urogenital tract infections in patients with weakened immunity (as part of combination therapy):
  Adults – 20 mL of syrup 3–4 times daily, treatment course from 2 weeks to 3 months;
  Children – daily dose calculated at 50 mg/kg (i.e., 1 mL syrup/kg) divided into 3–4 doses for 21 days (or 3 courses of 7–10 days each with equal breaks).

To restore immune system function and achieve a sustained immunomodulatory effect in patients with weakened immunity, the treatment course should last from 3 to 9 weeks.

Children.

The drug is indicated for children aged 1 year and older.

Overdose.

Cases of overdose have not been reported. Overdose may lead to increased serum and urinary uric acid concentrations. In case of overdose, gastric lavage and symptomatic therapy are indicated.

Side effects.

The most common side effect 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 a few days after discontinuation of therapy.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); very rare (≥ 1/10000); not known (cannot be estimated due to lack of data).

Very common:

Laboratory tests: increased blood uric acid level, increased urinary uric acid level.

Common:

Laboratory tests: increased blood urea nitrogen level, increased transaminase levels, increased alkaline phosphatase level in blood.

Nervous system disorders: headache, dizziness, increased fatigue, malaise.

Gastrointestinal disorders: nausea with or without vomiting, epigastric pain and discomfort.

Skin and subcutaneous tissue disorders: pruritus, skin rash.

Liver and biliary disorders: increased transaminase, alkaline phosphatase, or blood urea nitrogen levels.

Musculoskeletal and connective tissue disorders: arthralgia (joint pain).

Uncommon:

Nervous system disorders: nervousness, somnolence or insomnia, psychiatric disorders: irritability.

Gastrointestinal disorders: diarrhea, constipation.

Renal and urinary disorders: polyuria (increased urine volume).

Very rare:

Skin and subcutaneous tissue disorders: urticaria, erythema.

Immune system disorders: hypersensitivity reactions (including angioneurotic edema).

Gastrointestinal disorders: loss of appetite.

Shelf life. 3 years.

Shelf life after opening the bottle – 3 months.

Storage conditions.

Store in a dry place at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

120 ml, 180 ml, or 240 ml of syrup in an amber-yellow glass bottle with a white screw cap. One bottle per cardboard box. A measuring cup is provided with the package; each graduation corresponds to 2.5 ml of syrup.

Prescription category. Prescription only.

Manufacturer.

ABC Farmaceutici S.p.A.

Manufacturer's address and location of operations.

Via Canton Moretti, 29 (Località San Bernardo), 10015 – Ivrea (TO), Italy.

Tel. (+39) 0125240111, Fax (+39) 0125240179, e-mail: [email protected]