Groprinosin®

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

Composition:

Active substance: inosine pranobex;

One tablet contains 500 mg of inosine pranobex;

Excipients: potato starch, povidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: oval, biconvex tablets, white to cream-colored, with a score line on one side, 17 mm in length and 7 mm in width.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antiviral agents for systemic use. Direct-acting antiviral agents.
ATC Code J05A X05.

Pharmacological properties.

Pharmacodynamics.

Gropinозin® 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 T1-helpers, potentiating the induction of lymphoproliferative response in mitogen- or antigen-activated cells. Gropinозin® modulates cytotoxic activity of T-lymphocytes and natural killers, function of T8-suppressors and T4-helpers, and also increases the amount of immunoglobulin G and complement surface markers. Gropinозin® enhances synthesis of interleukin-1 (IL-1) and interleukin-2 (IL-2), regulates expression of IL-2 receptors. Gropinозin® significantly increases secretion of endogenous gamma-interferon and reduces production of interleukin-4 in the body. Gropinозin® enhances the activity of neutrophilic granulocytes, chemotaxis and phagocytosis by monocytes and macrophages. Gropinозin® inhibits viral synthesis by incorporating inosine orotic acid into polyribosomes of virus-infected cells and inhibits attachment of adenylate acid to viral mRNA.

Pharmacokinetics.

After oral administration of the drug at a dose of 1.5 g, the maximum plasma concentration of inosine pranobex is reached within 1 hour and amounts to 600 μg/mL. In the body, inosine pranobex is metabolized in the liver to form uric acid. The elimination half-life of 4-(acetylamino)benzoate is 50 minutes, and that of 1-(dimethylamino)-2-propanol is 3.5 hours. The metabolites are excreted by the kidneys.

Clinical characteristics.

Indications.

Groprinosin® is indicated for the treatment of decreased or dysfunctional cell-mediated immunity and clinical symptoms associated with such conditions:

• viral respiratory infections, primary and secondary immunodeficiency states;
• infections caused by herpesviruses: herpes simplex virus types 1 and 2, varicella-zoster virus; infections caused by cytomegalovirus and Epstein-Barr virus;
• genital warts (anogenital condylomata acuminata) — external lesions (excluding perianal areas and areas within the anal canal) — as monotherapy or as adjunctive therapy in combination with local or surgical treatment;
• papillomavirus infections of the skin and mucous membranes, vulva and vagina (subclinical) or cervix;
• viral hepatitis;
• severe or complicated measles;
• subacute sclerosing panencephalitis.

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 (e.g., allopurinol) or agents promoting uric acid excretion, including diuretics, particularly thiazide diuretics (such as hydrochlorothiazide, chlorthalidone, indapamide) or loop diuretics (e.g., furosemide, torasemide, ethacrynic acid).

Groprinosin® may be used after, but not simultaneously with immunosuppressants, due to a possible pharmacokinetic impact on desired therapeutic effects.

Concomitant administration with zidovudine (azidothymidine) increases the formation of the azidothymidine nucleotide through multiple mechanisms, including increased plasma bioavailability of zidovudine and enhanced intracellular phosphorylation in human blood monocytes. This results in potentiation of the effect of zidovudine.

Special precautions for use

During treatment with Groprinosin®, a temporary increase in serum and urinary uric acid levels may occur, especially in men and elderly individuals. However, these values usually remain within normal limits (up to 8 mg/dl or 0,420 mmol/l, respectively). The increase in uric acid levels is due to the catabolic metabolism of inosine in humans. This effect is not caused by a fundamental drug-induced alteration in enzyme function or renal clearance.

Therefore, Groprinosin® should be used with particular caution in patients with a history of gout, hyperuricemia, urolithiasis, or impaired renal function. Uric acid levels should be monitored throughout treatment in these patients.

Acute hypersensitivity reactions (angioedema, anaphylactic shock, urticaria) may occur in some individuals. In such cases, treatment with Groprinosin® should be discontinued immediately.

Prolonged use of the drug may increase the risk of kidney and gallbladder stone formation.

During long-term treatment, serum and/or urinary uric acid levels, liver function, blood counts, and renal function should be regularly monitored in all patients.

Use during pregnancy or breastfeeding

Pregnancy. Studies on the risk of fetal abnormalities or effects on fertility in humans have not been conducted. Groprinosin® should not be used during pregnancy unless the physician determines that the potential benefit outweighs the potential risk.

Breastfeeding. It is unknown whether inosine pranobex is excreted in human milk. Risk to the infant cannot be excluded. Breastfeeding should be discontinued during treatment.

Fertility. There are no data on the effect of the drug on human fertility. Animal studies have shown no effect on fertility.

Ability to affect reaction speed when driving or operating machinery

Groprinosin® has no effect or only a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product should be administered orally. The daily dose depends on body weight and severity of the disease; the dose should be evenly distributed throughout the day. To facilitate swallowing, the tablet may be crushed and dissolved in a small amount of liquid before administration.

Adults and elderly patients: The recommended dose is 50 mg/kg body weight (1 tablet per 10 kg body weight), usually 3 g/day (6 tablets), with a maximum dose of 4 g/day (8 tablets); administered orally, divided into 3–4 doses throughout the day.

Children from 1 year of age: The dose is 50 mg/kg body weight per day (1 tablet per 10 kg body weight for children with body weight up to 20 kg; for body weight above 20 kg, administer the adult dose).

Duration of Treatment

Acute diseases: For conditions with a short course, the treatment duration is 5 to 14 days. After symptom severity decreases, treatment should be continued for another 1–2 days or longer, depending on the physician’s decision.

Viral diseases with prolonged course: Treatment should be continued for 1–2 weeks after symptom severity decreases, or longer, depending on the physician’s decision.

Recurrent diseases: Initial treatment follows the same recommendations as for acute diseases. During maintenance therapy, the dose may be reduced to 500–1000 mg (1–2 tablets) per day. At the first signs of recurrence, the daily dose recommended for acute diseases should be resumed and continued for 1–2 days after symptoms disappear. The treatment course may be repeated several times if necessary, as recommended by the physician based on clinical assessment.

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 moderate symptoms: take for 60 days with a 30-day break;
• conditions with severe symptoms: take for 90 days with a 30-day break.

This treatment may be repeated if necessary; the patient’s condition should be monitored as in recurrent conditions.

Dosing for Special Indications

External genital warts (condylomata acuminata) or cervical canal papillomavirus infection: Take 2 tablets three times daily (3 g) as monotherapy or as an adjunct to local therapy or surgical treatment according to the following regimens:

• low-risk patients (patients with normal immunity or low risk of recurrence): the medicinal product is administered continuously for 14–28 days within a 3-month period, followed by a 2-month treatment break; continue until lesions decrease or disappear;
• high-risk patients * (patients with immunodeficiency or high risk of recurrence): during a 3-month period, the drug is administered 5 days per week for 2 consecutive weeks per month, or 5 days per week every other week.

This treatment may be repeated several times if necessary.

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 assessment of the patient’s condition and the need for continued therapy.

* High-risk factors for 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 due to:
• recurrent or chronic infections;
• sexually transmitted diseases;
• anticancer chemotherapy;
• chronic alcoholism;
• poorly controlled diabetes mellitus;
• atopy (hereditary predisposition to hypersensitivity);
• long-term contraceptive use (more than 2 years);
• erythrocyte folate levels ≤ 660 nmol/L;
• presence of 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 > 20 years;
• chronic smoking.

Children.

The medicinal product is administered to children from 1 year of age.

Overdose.

Cases of overdose have not been reported. Serious adverse effects, except for increased serum uric acid levels, are unlikely based on animal toxicity studies. Treatment is symptomatic and supportive.

Side effects

The most commonly occurring side effect observed during treatment with Groprinosin® in both adults and children is an increase in serum and urinary uric acid levels (usually remaining within normal limits), which typically returns to baseline values within several days after completion of treatment.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); frequency not known (cannot be estimated from available data).

Immune system disorders. Frequency not known: angioneurotic edema, hypersensitivity, urticaria, anaphylactic reaction.

Psychiatric disorders. Uncommon: nervousness.

Nervous system disorders. Common: headache, vertigo; uncommon: somnolence, insomnia; 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: rash, pruritus; frequency not known: erythema.

Musculoskeletal and connective tissue disorders. Common: arthralgia.

Renal and urinary disorders. Uncommon: polyuria.

General disorders. Common: fatigue, malaise.

Investigations. Very common: increased blood and urinary uric acid levels; common: increased blood levels of urea, transaminases, alkaline phosphatase.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets per blister; 2 (10 × 2) or 5 (10 × 5) blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sp. z o.o. "Gedeon Richter Poland".

Manufacturer's address.

5, ul. Ks. J. Poniatowskiego, Grodzisk Mazowiecki, 05-825, Poland.

Marketing authorization holder.

JSC "Gedeon Richter", Hungary.

Address of the marketing authorization holder.

H-1103 Budapest, 19–21, Demrédi utca, Hungary.