Laferobion

I N S T R U C T I O N for medical use of the medicinal product Laferobion® (Laferobionum®)

Composition:

Active substance: interferon alfa-2b;

1 vial contains: recombinant human interferon alfa-2b with activity of (1–18)·10⁶ IU, obtained from E. coli clone by hybridization of plasmid with human leukocyte interferon alpha-2b gene.

Excipients: sodium chloride, dextran-70, potassium dihydrogen phosphate, disodium phosphate dodecahydrate.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white powder or porous mass; hygroscopic. Like natural leukocyte interferon, it possesses three main types of biological activity: immunomodulatory, antiviral, and antitumor.

Pharmacotherapeutic group. Immunostimulants. Interferon alfa-2b.

ATC code L03AB05.

Pharmacological Properties.

Pharmacodynamics.

Recombinant interferon alfa-2b is a highly purified, water-soluble protein with a molecular weight of 19,300 daltons. The drug's activity is measured in international units (IU). International units are defined by comparing the activity of recombinant interferon alfa-2b with the activity of the WHO reference standard for human leukocyte interferon.

It exerts antiproliferative effects on tumor cells, as well as antiviral and immunomodulatory actions.

The action of interferon alfa-2b occurs through its binding to specific receptors on the cell surface membrane, initiating a complex of sequential intracellular reactions associated with the induction of several enzymes and the realization of cellular functions, namely the suppression of viral replication in infected cells, reduction of tumor cell proliferation, and induction of immunomodulatory processes (such as enhancement of macrophage phagocytic activity and increased specific cytotoxicity of lymphocytes against target cells).

Pharmacokinetics.

The pharmacokinetic properties of the drug have not been studied.

Clinical characteristics.

Indications. The drug should be used in the complex therapy of adults for:

• acute and chronic viral hepatitis B (moderate and severe forms);

• chronic hepatitis C;

• acute and chronic septic viral diseases;

• herpes infections of various localizations (herpes zoster, multiple cutaneous herpes eruptions, genital herpes infection);

• laryngeal papillomatosis;

• malignant melanoma, uveal melanoma, renal cell carcinoma, superficially localized bladder cancer, ovarian and breast cancer, Kaposi's sarcoma associated with HIV infection, chronic myeloid leukemia, hairy cell leukemia, non-Hodgkin's lymphomas, basal cell carcinoma, T-cell lymphoma of the skin (mycosis fungoides).

Contraindications.

• Hypersensitivity to the components of the drug;
• severe cardiovascular diseases (uncontrolled congestive heart failure, recent myocardial infarction, severe forms of arrhythmia);
• psoriasis;
• pronounced impairment of liver and/or kidney function, including metastases;
• epilepsy and other CNS disorders (including functional);
• chronic hepatitis in patients with progressive or decompensated liver cirrhosis;

• chronic hepatitis in patients receiving or who recently received immunosuppressive therapy (except for a short course of corticosteroids);

• autoimmune hepatitis or other autoimmune diseases in history;
• thyroid gland dysfunction in the patient;
• presence of severe visceral impairments in patients with Kaposi's sarcoma;
• combination therapy with telbivudine;
• myeloid hematopoiesis suppression;
• combination therapy with ribavirin when using Laferobion® as part of combination therapy for chronic hepatitis C.

Interaction with other medicinal products and other types of interactions. The drug should be used with caution when administered simultaneously with opioid medicinal products, analgesics, hypnotics, and sedatives (potentially exhibit myelosuppressive effects).

When used concomitantly with drugs metabolized via oxidation pathways (including xanthine derivatives – aminophylline and theophylline), possible influence of Laferobion® on oxidative metabolic processes should be considered. Serum theophylline concentration should be monitored if necessary – dosage regimen should be adjusted accordingly.

Rare cases of pulmonary infiltrates, pneumonitis, and pneumonia (some fatal) have been reported; lung injury has been more frequently reported when interferon alfa was used concomitantly with "shosai-ko-to" (a Chinese herbal medicine).

When the drug is used in combination with chemotherapeutic agents (cytarabine, doxorubicin, teniposide, cyclophosphamide), the risk of life-threatening toxic effects (in terms of severity and duration) increases.

When used concomitantly with zidovudine, the risk of developing neutropenia increases.

Special precautions for use.

Psychiatric disorders and central nervous system (CNS) disorders

In some patients during therapy with interferon alfa-2b and even after discontinuation of treatment, mainly within the following 6 months, severe adverse effects from the CNS have been observed, particularly: depression, suicidal thoughts and suicide attempts. In children and adolescents undergoing treatment with interferon alfa-2b in combination with ribavirin, suicidal thoughts and suicide attempts occurred more frequently than in adults (2.4% vs. 1%), during treatment and within 6 months after completion of therapy. As in adults, children and adolescents developed other psychiatric adverse effects (e.g., depression, emotional lability, and somnolence). Other CNS effects, including aggressive behavior (sometimes directed toward others, such as homicidal ideation), bipolar disorders, mania, confusion, and mental status changes, have been observed during treatment with alfa interferons. Patients should be closely monitored for symptoms of psychiatric disorders. If such symptoms occur, the physician should consider their potential severity and evaluate the need for appropriate treatment. If psychiatric symptoms do not resolve, worsen, or suicidal ideation develops, discontinuation of Laferobion® therapy is recommended, and appropriate psychiatric care should be provided.

Patients with clinical or historical evidence of severe psychiatric disorders

If treatment with interferon alfa-2b is necessary in adults with clinical or historical evidence of severe psychiatric disorders, it should be initiated only after appropriate individual psychiatric evaluation and treatment of the psychiatric condition.

Patients with alcohol or drug dependence

An increased risk of developing psychiatric disorders or exacerbation of pre-existing psychiatric disorders during interferon alfa therapy has been observed in patients with alcohol or drug dependence. If such patients require treatment with interferon alfa-2b, careful monitoring during and even after completion of therapy is required.

Adverse effects, including prolongation of coagulation parameters and liver function abnormalities

Moderate and severe adverse effects may require dose adjustment or, in some cases, discontinuation of Laferobion® therapy. Discontinuation of treatment is recommended in patients with chronic hepatitis who develop prolonged coagulation parameters, which may indicate hepatic insufficiency.

Close monitoring is required in any patient who develops liver function abnormalities during treatment with Laferobion®, and therapy should be discontinued if necessary.

Hypotension

Hypotension may occur during or within two days after therapy and may require additional treatment.

Need for adequate hydration

Patients undergoing treatment with Laferobion® should maintain adequate hydration, as dehydration may contribute to hypotension. In such cases, rehydration may be necessary.

Fever

Since fever may occur as part of the influenza-like syndrome commonly observed during interferon therapy, other causes of persistent fever should be ruled out.

Patients with debilitating conditions

Laferobion® should be used with caution in patients with chronic debilitating conditions, such as pulmonary diseases (e.g., chronic obstructive pulmonary disease) or in patients with diabetes prone to ketoacidosis. Close monitoring is also required in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Respiratory disorders

Rarely, patients receiving alfa interferon have developed pulmonary infiltrates, pneumonitis, and pneumonia, including fatal cases. The etiology of these events is not fully understood. These symptoms have been more frequently observed when "shosai-kotu" (a Chinese herbal preparation) was used concomitantly with alfa interferon. In the presence of fever, cough, dyspnea, or other respiratory symptoms, chest X-ray should be performed in all patients. If infiltrates or signs of impaired lung function are detected, patients should be closely monitored and alfa interferon should be discontinued if necessary. Although these symptoms were more commonly reported in patients with chronic hepatitis C treated with alfa interferon, they have also been observed in oncology patients undergoing alfa interferon therapy. Prompt discontinuation of alfa interferon and corticosteroid treatment may resolve pulmonary adverse effects.

Ocular adverse effects

Ocular adverse effects, including retinal hemorrhages, cotton-wool spots, and obstruction of the retinal artery or vein, have been observed in some patients after treatment with alfa interferons. All patients should undergo an ophthalmologic examination before starting therapy. Any patient reporting decreased visual acuity, visual field defects, or other ophthalmologic symptoms during treatment with Laferobion® should undergo immediate and complete ophthalmologic evaluation. Periodic ophthalmologic examinations during Laferobion® therapy are especially recommended in patients with conditions predisposing to retinopathy, such as diabetes mellitus or hypertension.

Treatment with the drug should be discontinued if new or worsening ophthalmologic disorders occur.

Somnolence, coma, and encephalopathy

In some patients, mainly elderly, receiving higher doses of the drug, episodes of somnolence and coma, including encephalopathy, have been observed. These effects are mostly reversible, with full recovery taking up to three weeks in some patients. Seizures are very rare with high-dose administration.

Patients with cardiovascular disorders

Close monitoring is required in adult patients with clinical or historical evidence of congestive heart failure, myocardial infarction, or arrhythmias. Patients with cardiovascular disease and/or advanced cancer should undergo ECG monitoring before and during treatment. Cardiac rhythm disturbances (mainly supraventricular arrhythmias) usually respond to conventional therapy, but discontinuation of Laferobion® may be necessary. Data on the use of combination therapy in children and adolescents with a history of cardiovascular disease are lacking.

Hypertriglyceridemia

Hypertriglyceridemia and exacerbation of pre-existing hypertriglyceridemia, sometimes severe, have been observed; therefore, lipid levels should be monitored.

Rejection of kidney and liver transplants

Preliminary data suggest that interferon alfa therapy may be associated with an increased incidence of kidney transplant rejection. Cases of liver transplant rejection have also been reported.

Autoantibodies and autoimmune disorders

Development of autoantibodies and autoimmune disorders has been observed during alfa interferon therapy. Patients predisposed to autoimmune disorders are at increased risk. Patients with signs of autoimmune disorders require close monitoring and reassessment of the benefit/risk ratio of continued interferon therapy. Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been observed in patients with chronic hepatitis C treated with interferon. VKH syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral therapy should be discontinued and corticosteroid treatment considered.

Concomitant chemotherapy

The use of Laferobion® in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) increases the risk of life-threatening toxicity. The most common life-threatening adverse effects include mucositis, diarrhea, neutropenia, renal failure, and electrolyte disturbances. Due to the risk of increased toxicity, careful dose selection of Laferobion® is required when used concomitantly with chemotherapeutic agents. If Laferobion® is used with hydroxyurea, the frequency and severity of cutaneous vasculitis may increase.

Chronic hepatitis C

Combination therapy with ribavirin (when Laferobion® is used as part of combination therapy for chronic hepatitis C)

All patients with chronic hepatitis C underwent liver biopsy before enrollment in clinical trials, but in certain cases (e.g., patients with viral genotypes 2 and 3), treatment may be initiated without histological confirmation. Current clinical guidelines should be followed regarding management strategies for such patients.

Monotherapy

Thyroid disorders—hypothyroidism or hyperthyroidism—occurred infrequently in adult patients receiving interferon alfa-2b for chronic hepatitis C (in 2.8% of patients in clinical trials). Thyroid function abnormalities were managed with standard therapy. The mechanism by which Laferobion® may affect thyroid status is unknown. Serum thyroid-stimulating hormone (TSH) levels should be measured before initiating Laferobion® therapy. If abnormalities are detected, appropriate treatment should be initiated. If TSH levels can be maintained within the normal range with medication, treatment with Laferobion® may proceed. If symptoms of thyroid dysfunction develop during therapy, TSH levels should be measured. Laferobion® therapy may be continued if TSH levels remain within the normal range with medication. Discontinuation of Laferobion® does not lead to recovery of thyroid function impaired during treatment.

HIV/hepatitis C virus co-infection

In patients co-infected with HIV and receiving highly active antiretroviral therapy (HAART), the risk of lactic acidosis increases. Caution should be exercised when adding Laferobion® and ribavirin to HAART. In patients receiving Laferobion® and ribavirin in combination with zidovudine, the risk of anemia is increased.

In co-infected patients with cirrhosis receiving HAART, the risk of hepatic decompensation and death is increased. Additional use of alfa interferons, alone or in combination with ribavirin, further increases the risk in this patient group.

Hepatitis B and C virus co-infection

Cases of hepatitis B reactivation (some with severe outcomes) have been reported in patients co-infected with hepatitis B and C viruses receiving interferon. The frequency of reactivation is low. All patients should be tested for hepatitis B before initiating interferon therapy for hepatitis C. Monitoring of patients co-infected with hepatitis B and C should follow current clinical guidelines.

Dental and periodontal disorders

Dental and periodontal disorders, potentially leading to tooth loss, have been reported in patients receiving combination therapy with Laferobion® and ribavirin. In addition, dry mouth may cause damage to teeth and oral mucosa during prolonged use of Laferobion® and ribavirin. Patients should maintain good oral hygiene and undergo regular dental check-ups. Furthermore, vomiting may occur in some patients. If vomiting occurs, thorough rinsing of the oral cavity is recommended.

Laboratory tests

Standard hematological and biochemical blood tests (complete blood count with differential, platelet count, electrolytes, liver enzymes, serum protein, bilirubin, and serum creatinine) are mandatory for all patients before and during systemic therapy with Laferobion®.

During therapy for chronic hepatitis B or C, the following laboratory monitoring schedule is recommended: weeks 1, 2, 4, 8, 12, 16, and then every two months throughout the treatment course. If ALT levels increase to twice or more above pre-treatment values, Laferobion® therapy may be continued provided there are no signs of hepatic insufficiency. In such cases, ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin should be monitored every two weeks.

In patients with malignant melanoma, liver function and leukocyte count (with differential) should be monitored weekly during induction and monthly during maintenance therapy.

Use during pregnancy or breastfeeding. There are no adequate data on the use of interferon alfa-2b in pregnant women. Animal studies have shown toxic effects on the fetus; the potential risk in humans is unknown. The use of the drug during pregnancy or breastfeeding is contraindicated. Women of childbearing potential should use effective contraception.

There is no information on the excretion of this drug's components in human milk.

Due to the potential risk to the infant, the decision to discontinue breastfeeding or to discontinue the drug should be made considering the necessity of the drug for the mother.

Ability to affect reaction speed when driving or operating machinery. The ability to drive or operate machinery may be impaired due to weakness, somnolence, or disturbances of consciousness that may occur during treatment. If such disorders occur during therapy, patients should refrain from driving or operating machinery.

Administration and Dosage

The drug should be administered as a solution. The solution of Laferobion® is administered intravenously (by drip), intramuscularly, subcutaneously, intradermally, intraperitoneally, or intravesically.

Recommended treatment regimens:

Acute viral hepatitis B: 1 million IU intramuscularly twice daily (in severe cases – 2 million IU twice daily) for 10 days; thereafter, depending on the patient's clinical status, treatment may be continued for 2–3 weeks according to the above regimen or 1 million IU twice weekly for several weeks.

Chronic viral hepatitis B: 3–4 million IU intramuscularly, 3 times per week for 2 months.

Chronic hepatitis C: 3 million IU subcutaneously 3 times per week (every other day), either in combination with ribavirin or as monotherapy (in cases of contraindications or intolerance to ribavirin). The treatment duration is 3–4 months, followed by HCV RNA testing. Continue therapy if HCV RNA is undetectable. Monotherapy course lasts 12–18 months; in combination with ribavirin – 6 months. For genotype 1 virus and high viral load prior to therapy, if HCV RNA is undetectable in serum by the end of 6 months of treatment, combination therapy may be extended for another 6 months. However, consider negative prognostic factors such as age over 40 years, male gender, and progressive fibrosis.

Herpetic infections:

Herpes zoster: daily 1 million IU intramuscularly + 2 million IU in 5 ml of 0.9% sodium chloride solution administered subcutaneously at multiple points around the affected area. Treatment duration: 5–7 days.

Cutaneous herpes eruptions: daily intramuscular or subcutaneous administration (around the lesion) at a dose of 2 million IU. Treatment may be combined with local application (topical applications) to herpetic papules. The treatment course is determined by the physician.

Genital herpes infection: daily intramuscular administration at a dose of 2 million IU, combined with local application (as topical applications) to the affected areas. The treatment course is determined by the physician.

Laryngeal papillomatosis: 3 million IU/m² subcutaneously 3 times per week (every other day) for 6 months or longer. Adjust dose based on tolerability. Begin treatment after surgical (laser) removal of tumor tissue.

Malignant melanoma: as adjunct to surgical treatment and for induction of remission, administer intravenously 20 million IU/m² (infusion over 20 minutes) 5 times per week for 4 weeks. Maintenance therapy: subcutaneous 10 million IU/m² 3 times per week (every other day) for 48 weeks.

In case of severe adverse effects, particularly granulocyte count reduction (below 500/mm³) or elevated ALT/AST (exceeding the upper normal limit by 5 times), discontinue the drug until parameters normalize. Resume treatment at half dose. If intolerance persists and granulocyte count drops to 250/mm³ or ALT and/or AST activity increases (exceeding the upper normal limit by 10 times), discontinue the drug.

Uveal melanoma: (when treated in combination with photodestruction of the tumor and beta-applications), the following regimen may be used: peribulbar injection of 1 million IU (diluted in 1 ml of water for injections) daily for 10 days; repeat 10-day courses after 20 days, twice. Total treatment course: 48 weeks. Repeat courses after 45 days may be necessary.

Renal cell carcinoma: intramuscularly 3 million IU daily for 10 days; total course dose: 30 million IU. Repeat courses every 3–5 weeks for 6 months, then every 1.5–2 months for 1 year. As induction therapy: 10 million IU/m² (up to 18 million IU/m² per day) intramuscularly or subcutaneously. Increase dose by 3 million IU/m² every 3 days (first 3 days: 3 million IU/m², next 3 days: 6 million IU/m², next 3 days: 9 million IU/m², etc., up to 18 million IU/m²). Adjust doses based on tolerability. With good tolerability, maximum dose may reach 36 million IU/m². Induction therapy duration: 3 months. After this, decide on discontinuation or continuation of treatment in case of remission or disease stabilization.

For maintenance therapy, administer the same doses 3 times per week for at least 6 months.

Superficial bladder cancer: intravesical administration of 30–50 million IU weekly for 8–12 weeks. For carcinoma in situ: 60–100 million IU per instillation weekly for 12 weeks. Before administration, the patient should refrain from fluid intake for 8 hours. Empty the bladder before drug administration. Administer the drug sterilely via catheter into the bladder cavity, where it should remain for 2 hours. The patient should change body position every 15 minutes during this time (to ensure better contact between the drug and bladder mucosa). After 2 hours, empty the bladder.

Ovarian cancer: intraperitoneal (via drainage) during surgery and for the next 5 days at 5 million IU. Then intramuscularly 3 million IU daily for 10 days between chemotherapy cycles. Total course dose: 90 million IU. Subsequent courses (3 million IU daily for 10 days) may be administered every 2–3 months for 1–1.5 years.

Breast cancer: intramuscularly 3 million IU daily for 10 days. Repeat courses for 1 year with intervals of 1.5–2 months, then 2–3 months (depending on clinical status). Alternating courses of Laferobion therapy with chemotherapy (or radiotherapy) is advisable.

Kaposi's sarcoma associated with HIV infection: possible treatment regimens:

• Intramuscularly 3 million IU daily for 10 days, combined with chemotherapy using prosidin. Repeat courses once monthly for 6 months.
• Intravenous infusion over 30 minutes at 50 million IU (30 million IU/m²) daily for 5 consecutive days or every other day, followed by a minimum 9-day break before starting a new 5-day course. This regimen may be maintained continuously, except in cases of rapid disease progression or marked intolerance to the drug.

Chronic myeloid leukemia: subcutaneously 3 million IU/m² daily or every other day, gradually increasing the dose under medical supervision to 5 million IU/m² daily or every other day until complete hematological remission is achieved (leukocyte count in peripheral blood not exceeding 10·10⁹/L) or for up to 18 months. After achieving complete hematological remission, continue treatment until complete cytogenetic remission is achieved (which may occur only 1–2 years after treatment initiation in some patients). Begin treatment as early as possible. If leukocyte count exceeds 50·10⁹/L, initiate therapy with standard hydroxyurea dose, then switch to Laferobion®.

Hairy cell leukemia: intramuscularly or subcutaneously 2–3 million IU/m² until remission is achieved, then 3 times per week (every other day). Average treatment duration: 12 months. Adjust dose based on tolerability.

Non-Hodgkin's lymphomas: intramuscularly or subcutaneously 3 million IU/m² (gradually increasing dose up to 5 million IU/m² under physician supervision) 3 times per week (as adjunct to chemotherapy), or 3 million IU 3 times per week for 12–18 months (as maintenance therapy during remission after chemotherapy).

Basal cell carcinoma: 10 million IU (dissolved in 1 ml of water for injections) injected into the base and center of the tumor (using a 1 ml syringe). If the affected area is less than 2 cm², administer 0.15 ml of the drug solution (1.5 million IU) 3 times per week (every other day) for 3 weeks. Total dose should not exceed 13.5 million IU. If the affected area is 2–10 cm², the drug dose should be 0.5 million IU/cm² (but not less than 1.5 million IU for the first injection). Administer 3 times per week (every other day) for 3 weeks. Treat only one lesion area at a time. If no positive dynamics (appearance, size of lesion, degree of redness, biopsy results) is observed after 2–3 months of treatment, consider surgical intervention.

T-cell lymphoma (mycosis fungoides) in ulcerative stage: intradermally (into the superficial dermal layer beneath the plaque or ulcer) 1–2 million IU (dissolved in 0.5 ml of water for injections) 3 times per week for 4 weeks. Before injection, disinfect the affected area with an alcohol-soaked cotton swab. Administer the solution using a fine needle (30-gauge) and a 1 ml syringe. The needle should be almost parallel to the skin surface during injection. Avoid deeper (subcutaneous) administration.

Preparation of the drug solution

Prepare the solution immediately before administration. Use water for injections as solvent when preparing the solution for subcutaneous, intradermal, or intramuscular administration. Dissolve the vial contents in 1 ml of water for injections.

When preparing the solution for intraperitoneal or intravesical administration, use 0.9% sodium chloride solution as solvent (calculated so that the concentration of Laferobion® in the solution is not less than 0.3 million IU/ml).

Preparation and administration of intravenous infusion

Begin infusion of 0.9% sodium chloride solution (at 200 ml/hour) 30 minutes before starting Laferobion® infusion and complete it immediately before drug administration.

To prepare the infusion solution, first dissolve Laferobion® in water for injections (1 ml water per dose to be administered). Then withdraw the required amount of drug (the dose in 1 ml of aqueous solution) and add it to 50 ml of 0.9% isotonic sodium chloride solution. Administer the prepared solution intravenously by drip over 30 minutes. After completing Laferobion® infusion, continue infusion of 0.9% isotonic sodium chloride solution (at 200 ml/hour) for 10 minutes.

Children. Experience with use in children is lacking.

Overdose. Cases of overdose with Laferobion® have not been reported. However, as with any drug overdose, symptomatic therapy is recommended, with monitoring of vital organ functions and careful patient observation.

Adverse Reactions

If Laferobion® is used in combination with ribavirin in patients with chronic hepatitis C, refer also to the ribavirin prescribing information for adverse effects associated with ribavirin use.

The most commonly observed adverse effects in patients with hairy cell leukemia were fever, fatigue, headache, and myalgia. Fever and fatigue resolved within 72 hours after discontinuation or temporary interruption of the drug.

Adults

When interferon alfa-2b was used for the treatment of hepatitis C, patients received a one-year course of therapy with interferon alfa-2b alone or in combination with ribavirin. All patients received 3 million IU of interferon alfa-2b three times weekly.

Table 1 presents treatment-related adverse effects observed in previously untreated patients undergoing one-year therapy. Most adverse effects were primarily mild to moderate in severity.

Table 1

Adverse reactions occurring during clinical studies or post-marketing use of interferon alfa-2b as monotherapy or in combination with ribavirin

*These adverse effects are common only with interferon alfa-2b monotherapy.

§See section "Special precautions".

#Properties for the class of interferon alfa-2b drugs, see subsection Pulmonary arterial hypertension.

Adverse reactions observed in patients with hepatitis C are typical for interferon alfa-2b use in other indications, with increased frequency of occurrence at higher doses. For example, when high doses of interferon alfa-2b are used in adjuvant therapy of melanoma patients, adverse reactions such as fatigue, fever, myalgia, neutropenia, anemia, anorexia, nausea and vomiting, diarrhea, chills, flu-like symptoms, depression, alopecia, taste disturbance, and dizziness occur more frequently than in clinical trials of hepatitis C patients. The severity of adverse effects also increases with high-dose therapy, compared to mild and moderate severity observed with lower doses. Adverse effects are usually managed by dose adjustment.

Cardiovascular adverse effects, particularly arrhythmias, mainly occur in patients with pre-existing cardiovascular disease or prior treatment with cardiotoxic agents. Cardiomyopathy, which resolves upon discontinuation of interferon alfa-2b therapy, has been rarely observed in patients without underlying heart disease.

Cases of pulmonary arterial hypertension have been reported with the use of interferon alfa-2b, particularly in patients with risk factors for pulmonary arterial hypertension (such as portal hypertension, HIV infection, liver cirrhosis). Adverse events were reported at various time intervals, usually several months after initiation of interferon alfa-2b therapy.

A broad range of autoimmune and immune-mediated disorders have been observed with the use of alpha-interferons, including thyroid dysfunction, systemic lupus erythematosus, rheumatoid arthritis (onset or exacerbation), hemorrhagic and thrombotic thrombocytopenic purpura, vasculitis, and neuropathy, including mononeuropathy.

Clinically significant laboratory abnormalities, more commonly occurring at doses exceeding 10 million IU per day, include decreased granulocyte and leukocyte counts; reduced hemoglobin levels and thrombocyte counts; increased levels of alkaline phosphatase, LDH, serum creatinine, and serum urea nitrogen. Moderate, usually reversible pancytopenia has also been observed. Elevated ALT/AST levels as abnormal findings have been observed in some patients without hepatitis C, as well as in some patients with chronic hepatitis B, coinciding with viral DNA polymerase clearance.

The adverse reactions listed in Table 2 are observed in adult patients receiving interferon alfa-2b in combination with ribavirin.

Table 2

Adverse reactions observed during interferon alfa-2b therapy in combination with ribavirin

§See section "Special instructions for use".

Reporting of adverse reactions

Reporting of adverse reactions after registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any possible adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions. Store in a dry, light-protected place at a temperature of 2 to 8 ºC.

Keep out of reach of children.

Packaging. Lyophilisate for solution for injection: 1,000,000 IU or 3,000,000 IU in vials, pack size 10 (5×2);

6,000,000 IU in vials, pack size 5, supplied with solvent (2 ml) in ampoules, pack size 5;

18,000,000 IU in vial, pack size 1, supplied with solvent (2 ml) in ampoules, pack size 1.

Vials with lyophilisate or vials with lyophilisate and ampoules with solvent in a blister. One or two blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LLC "FZ "BIOFARMA", Ukraine.

Manufacturer's location and address of its production site.

37 Kyivska St., Bila Tserkva, Kyiv Oblast, 09100, Ukraine.