Ziprin

INSTRUCTION for medical use of the medicinal product ZIPRIN

Composition:
Active substance: inosine pranobex;
1 tablet contains 500 mg of inosine pranobex.
Excipients: maize starch, povidone K-25, magnesium stearate, mannite (E 421).

Medicinal form: Tablets.

Main physical and chemical properties:
Round-shaped tablets, from nearly white to yellowish-white in color, with a biconvex surface and a slight specific odor.

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

Pharmacological properties

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

Inosine pranobex modulates cytotoxic activity of T-lymphocytes and natural killer cells, function of T8-suppressor and T4-helper cells, and increases the amount of immunoglobulin G and complement surface markers.

Inosine pranobex enhances synthesis of interleukin-1 (IL-1) and interleukin-2 (IL-2), and regulates expression of IL-2 receptors. The substance significantly increases secretion of endogenous gamma-interferon and reduces formation of interleukin-4 in the body.

The drug enhances the activity of neutrophilic granulocytes, chemotaxis, and phagocytosis by monocytes and macrophages.

Inosine pranobex inhibits viral replication by incorporating inosinoribotic acid into ribosomes of virus-infected cells and by inhibiting adenylic acid attachment 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-(acetylamino)benzoate is 50 minutes; that of 1-(dimethylamino)-2-propanol is 3.5 hours. The metabolites are excreted by the kidneys.

Clinical characteristics

Indications:
Ziprin is indicated for the treatment of conditions associated with impaired or dysfunctional cell-mediated immunity and related clinical symptoms, including:

• Viral respiratory infections, primary and secondary immunodeficiency states;
• Herpesvirus infections: 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 inside 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; acute gout, urolithiasis, severe renal insufficiency (stage III), hyperuricemia.

Interaction with other medicinal products and other forms of interaction:
The drug should be used with caution when co-administered 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).

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

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

Special precautions:
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 does not result from a fundamental drug-induced alteration 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. Uric acid levels should be monitored during treatment in these patients.

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

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

Use during pregnancy or breastfeeding

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

Breastfeeding:
It is unknown whether inosine pranobex is excreted in breast 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 influence reaction speed when driving or operating machinery:
Ziprin has no effect or negligible effect on the ability to drive or operate machinery.

Method of administration and dosage:
The medicinal product should be taken orally. The daily dose depends on body weight and severity of 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.

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 10 kg body weight), usually 3 g/day (6 tablets), maximum dose: 4 g/day (8 tablets); administered orally, divided into 3–4 doses per day.

Children from 1 year of age:
Dose: 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, dose as for adults).

Duration of treatment

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

Chronic viral diseases:
Treatment should be continued for 1–2 weeks after reduction in symptom severity or longer, depending on 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 symptom resolution. Treatment courses may be repeated several times as necessary, according to physician’s recommendation 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: 30 days of treatment followed by a 60-day break;
• Conditions with moderate symptoms: 60 days of treatment followed by a 30-day break;
• Conditions with severe symptoms: 90 days of treatment followed by a 30-day break.

This treatment may be repeated as necessary; patient status should be monitored as in recurrent conditions.

Dosage for special indications

External genital warts (anogenital condylomata acuminata) or cervical canal papillomavirus infection:
Take 2 tablets three times daily (3 g) as monotherapy or as 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 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): administer 5 days per week for 2 consecutive weeks each month, or 5 days per week every other week, over a 3-month period.

This treatment may be repeated several times as necessary.

Subacute sclerosing panencephalitis:
Daily dose: 100 mg/kg body weight, maximum dose: 3–4 g/day. Treatment is long-term and continuous, with regular assessment of patient status and 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 use of contraceptives (more than 2 years);
• Erythrocyte folate level ≤660 nmol/L;
• Presence of 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.

Children:
The medicinal product may be used in children from 1 year of age.

Overdose:
Cases of overdose have not been reported. 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 most common adverse effect 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 (≥ 1/1,000, < 1/100);
Frequency not known (cannot be estimated from 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 of the medicinal product via the Automated Information System for Pharmacovigilance 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: 10 tablets per blister, 4 blisters per carton.
Prescription status: Prescription only.
Manufacturer: LLC "DKP "Pharmaceutical Factory".
Address of manufacturer and location of its business activities: 4, Korolova St., village Stanishivka, Zhytomyr district, Zhytomyr region, 12430, Ukraine.