Groviral 1000

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GROVIRAL 1000 (GROVIRAL 1000)

Composition:
Active substance: inosine pranobex;
1 tablet contains inosine pranobex 1000 mg.
Excipients: maize starch, povidone K-25, magnesium stearate, mannitol (E 421).

Pharmaceutical form.
Tablets.

Main physicochemical properties:
Oval elongated tablets with a biconvex surface, scored on both sides, from almost white to yellowish-white in color, with a slight specific odor.

Pharmacotherapeutic group.
Anti-infective agents for systemic use.
Antiviral agents for systemic use.
Direct-acting antiviral agents.
ATC code: J05AX05.

Pharmacological properties.

Pharmacodynamics.
Groviral 1000 is an antiviral agent with immunomodulatory properties. The medicinal product corrects deficiency or dysfunction of cellular immunity by inducing maturation and differentiation of T-lymphocytes and T1-helper cells, and potentiating lymphoproliferative response in mitogen- or antigen-activated cells.

Inosine pranobex modulates cytotoxic activity of T-lymphocytes and natural killer cells, function of T8-suppressors and T4-helpers, and increases immunoglobulin G levels and complement surface markers. The drug enhances synthesis of interleukin-1 (IL-1) and interleukin-2 (IL-2), regulates expression of IL-2 receptors. Inosine pranobex significantly increases secretion of endogenous gamma-interferon and reduces formation of interleukin-4 in the body. The preparation enhances activity of neutrophil granulocytes, chemotaxis, and phagocytosis of monocytes and macrophages.

Inosine pranobex inhibits viral replication by incorporating inosinic acid into polyribosomes of virus-infected cells and inhibiting adenylic acid binding to viral mRNA.

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

Clinical characteristics.

Indications.
Groviral 1000 is indicated for the treatment of reduced or dysfunctional cell-mediated immunity and clinical symptoms associated with the following conditions:

• Viral respiratory infections, primary and secondary, and immunosuppressive 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 (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, urolithiasis, severe renal insufficiency stage III, hyperuricemia.

Interaction with other medicinal products and other forms of interaction.
Use with caution when co-administering 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).

Groviral 1000 may be used after, but not simultaneously with immunosuppressants, due to possible pharmacokinetic interference with desired therapeutic effects.

When used concomitantly with zidovudine (azidothymidine), formation of azidothymidine nucleotide is increased via multiple mechanisms, including increased bioavailability of azidothymidine in plasma and enhanced intracellular phosphorylation in human blood monocytes. This results in potentiation of zidovudine's effect.

Special precautions for use.
During treatment with inosine pranobex, transient elevation of 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 0.420 mmol/l, respectively). The increase in uric acid levels is due to catabolic metabolism of inosine in humans. This occurs not due to drug-induced fundamental changes in enzyme function or renal clearance. Therefore, the medicinal product should be used with particular caution in patients with gout, hyperuricemia, history of urolithiasis, or impaired renal function. During treatment, uric acid levels should be monitored in these patients.

Acute hypersensitivity reactions (angioneurotic edema, anaphylactic shock, urticaria) may occur in some individuals. In such cases, therapy with inosine pranobex should be discontinued.

With prolonged use of the drug, there is a risk of kidney and gallbladder stone formation. During long-term treatment, serum uric acid levels and/or urine uric acid, liver function, blood count, and renal function should be regularly monitored in all patients.

Use during pregnancy or breastfeeding.

Pregnancy.
Studies on the risk of fetal abnormalities and fertility impairment in humans have not been conducted. Groviral 1000 should not be used during pregnancy except when the physician decides that the potential benefit outweighs the potential risk.

Breastfeeding.
It is unknown whether inosine pranobex passes into breast milk. Risk to infants cannot be excluded. Breastfeeding should be discontinued during treatment.

Fertility.
There are no data on the effect of the medicinal product on fertility in humans. Animal studies showed no effect on fertility.

Ability to affect reaction speed when driving or operating machinery.
Groviral 1000 has no effect or negligible effect on the ability to drive or operate machinery.

Method of administration and dosage.
The medicinal product is administered orally. The daily dose depends on body weight and severity of disease; the dose should be evenly distributed throughout the day. For easier swallowing, the tablet may be crushed and dissolved in a small amount of liquid. If lower doses are required, inosine pranobex in another pharmaceutical form should be used.

Adults and elderly patients:
Recommended dose: 50 mg/kg body weight (1 tablet per 20 kg), usually 3 g/day (3 tablets), maximum dose — 4 g/day (4 tablets); administered orally, divided into 3–4 doses per day.

Children with body weight over 20 kg:
Administer Groviral 1000 at the same dose as for adults — 50 mg/kg body weight per day.

Children with body weight up to 20 kg and aged 1 year and older:
Use inosine pranobex at an appropriate dosage — daily dose of 50 mg/kg body weight per day (1 tablet of 500* mg per 10 kg body weight).

Duration of treatment.

Acute diseases:
For diseases with short duration, treatment course lasts 5 to 14 days. After reduction of disease symptoms, treatment should be continued for another 1–2 days or longer, depending on the physician's decision.

Chronic viral diseases:
Treatment should be continued for 1–2 weeks after reduction of disease symptoms or longer, depending on the physician's decision.

Recurrent diseases:
At the initial stage of treatment, the same recommendations apply as for acute diseases. During maintenance therapy, the dose may be reduced to 500*–1000 mg 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 symptom disappearance. The treatment course may be repeated several times, if necessary, according to the physician's recommendation based on clinical assessment.

Chronic diseases:
The medicinal product should be prescribed at a daily dose of 50 mg/kg body weight according to the following regimens:

• Asymptomatic diseases: take for 30 days followed by a 60-day break;
• Diseases with moderately expressed symptoms: take for 60 days followed by a 30-day break;
• Diseases with severe symptoms: take for 90 days followed by a 30-day break.

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

Dosage in special indications.

External genital warts (condylomata acuminata) or papillomavirus infection of the cervical canal:
Administer 1 tablet 3 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): administer continuously for 14–28 days every month for a period of 3 months, followed by a 2-month treatment break; continue until lesions decrease or disappear;
• High-risk patients ** (patients with immunodeficiency or high risk of recurrence): administer 5 days per week for 2 consecutive weeks each month, or 5 days per week every other week, for a period of 3 months.

This treatment may be repeated several times if necessary.

Subacute sclerosing panencephalitis:
Daily dose is 100 mg/kg body weight, maximum dose — 3–4 g/day. Treatment is long-term, continuous, with regular assessment of the patient's condition and need for continued therapy.

* Use inosine pranobex at appropriate dosage.
** 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 use of contraceptives (longer 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 skin warts in childhood;

• Age > 20 years;

• Chronic smoking.

Children.
The medicinal product is used in children with body weight from 20 kg.

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

Adverse reactions.
The only adverse effect commonly observed during treatment with inosine pranobex in both adults and children is increased serum and urinary uric acid levels (usually remaining within normal limits), which typically return to baseline values within several days after treatment ends.

Frequency of adverse reactions is defined 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).

Reporting suspected adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are required to report all 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: 3 years.
Storage conditions: Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.
Packaging: 6 tablets per blister, 5 blisters per carton.
Prescription status: Prescription only.
Manufacturer: LLC "DKP "Pharmaceutical Factory".
Manufacturer's address: Stanishivka village, Zheltoshivska St., b. 4, Zheltoshiv district, Zhytomyr region, 12430, Ukraine.
Marketing Authorization Holder: Limited Liability Company "Baum Pharma GmbH Representation".
Address of the Marketing Authorization Holder: 66 Shyroka St., Lviv, 79052, Ukraine.