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

Composition:

Active substance: interferon alfa-2b;

1 vial contains 3 million IU or 5 million IU of recombinant human interferon alfa-2b;

Excipients: glycine, human albumin, sodium dihydrogen phosphate anhydrous, disodium hydrogen phosphate dodecahydrate.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white or almost white powder, homogeneous and compact.

Pharmacotherapeutic group. Immunostimulants. Interferons. Interferon alfa-2b.

ATC code L03A B05.

Pharmacological Properties

Pharmacodynamics

Recombinant human interferon alfa-2b belongs to the group of endogenous low-molecular-weight proteins with antiviral, immunomodulatory, and antiproliferative properties. The active ingredient of Bioferon – recombinant human interferon alfa-2b – is a highly purified protein consisting of 165 amino acids with a molecular weight of 19,000 daltons. The drug is produced from a clone of E. coli via plasmid hybridization with the gene of human leukocytes encoding interferon synthesis.

The antiviral effect of the drug is due to its interaction with specific membrane receptors, induction of mRNA synthesis, and ultimately, the synthesis of proteins that interfere with normal viral replication or release. The immunomodulatory activity of the drug is associated with stimulation of phagocytosis, which enhances the production of antibodies and lymphokines. The drug also exerts antiproliferative effects on malignant tumor cells.

Pharmacokinetics

Absorption: When administered directly into the pathological area, the concentration of interferon in blood plasma is usually below the detection level, although systemic effects may occasionally occur even with this route of administration. After intramuscular or subcutaneous administration, over 80% of the administered dose enters systemic circulation.

Biotransformation: Complete biotransformation occurs in the kidneys. Interferon alfa is filtered in the glomeruli and undergoes rapid proteolytic degradation during reabsorption in the tubules.

Elimination half-life: 2–3 hours after intramuscular or subcutaneous administration. With daily intramuscular administration, accumulation may occur.

Time to reach maximum concentration: 3–12 hours after single intramuscular or subcutaneous administration.

Elimination occurs primarily via the kidneys; metabolites are almost completely reabsorbed in the renal tubules. Only a small amount of administered interferon alfa remains unchanged in systemic circulation.

Clinical characteristics.

Indications.

Chronic hepatitis B

Treatment of adult patients and children aged 1 year and older with chronic hepatitis B associated with hepatitis B virus replication (presence of hepatitis B virus DNA (HBV-DNA) and hepatitis B e antigen (HBeAg), elevated alanine aminotransferase (ALT) levels, and histologically proven active liver inflammation and/or fibrosis).

Chronic hepatitis C

In adults: compensated form of chronic hepatitis C in patients with elevated serum transaminase activity and presence in blood serum of hepatitis C virus RNA (HCV) or antibodies against HCV.

Typically, for the treatment of chronic hepatitis C in patients with compensated disease who have not previously received interferon alpha therapy, Bioferon should be used in combination with ribavirin.

In children: Bioferon in combination with ribavirin is indicated for the treatment of children aged 3 years and older with chronic hepatitis C, provided that liver disease is compensated, prior therapy of this kind has not been administered, and HCV RNA is detectable in blood serum. The decision to use this therapy should be made on an individual basis, taking into account signs of disease progression manifested by liver inflammation and fibrosis, as well as prognostic factors for response to therapy, HCV genotype, and viral load.

Hairy cell leukemia

Hairy cell leukemia in patients aged 18 years and older, whether or not splenectomy has been performed.

Chronic myeloid leukemia

Monotherapy: chronic myeloid leukemia in adult patients with the Philadelphia chromosome or bcr/abl translocation.

Combination therapy: administration of Bioferon in combination with cytarabine (Ara-C) during the first 12 months leads to a significant increase in the frequency of major cytogenetic responses and significantly improves three-year survival compared to monotherapy with interferon alfa-2b.

Multiple myeloma

As a maintenance therapy in patients with multiple myeloma after achieving objective remission (reduction of myeloma protein content by more than 50%) as a result of induction chemotherapy.

Follicular lymphoma

Follicular lymphoma in patients aged 18 years and older with high tumor burden, as an adjuvant agent in combination with induction chemotherapy (e.g., CHOP regimen).

High tumor burden is defined as the presence in the patient of at least one of the following features: bulky tumor mass (>7 cm); involvement of at least three nodes (each >3 cm); presence of systemic symptoms (weight loss >10%, fever >38°C lasting >8 days, excessive night sweats); splenomegaly (spleen edge below umbilicus); compression of vital organs; involvement of orbital or epidural regions; presence of serous effusion; leukemization of the process.

Carcinoid tumors

Carcinoid tumors with metastases to lymph nodes or liver and "carcinoid syndrome."

Malignant melanoma

Malignant melanoma in patients aged 18 years and older with a high risk of systemic recurrence (within 56 days after surgery), i.e., with primary or recurrent lymph node involvement, as an adjuvant therapy following surgical treatment.

Genital warts

Genital warts involving the external genitalia and perianal area in patients aged 18 years and older.

AIDS-associated Kaposi's sarcoma

AIDS-associated Kaposi's sarcoma in patients aged 18 years and older. The likelihood of response to Bioferon therapy increases in patients without systemic symptoms, with limited lymphadenopathy, and relatively intact immune system, considering the total CD4 cell count.

Contraindications.

Individual hypersensitivity to the drug or its ingredients listed in the section "Composition";
history of heart disease, such as uncontrolled congestive heart failure, recent myocardial infarction, severe arrhythmias;
severe impairment of kidney or liver function, including that caused by tumor metastases;
epilepsy and/or central nervous system (CNS) disorders, see section "Special precautions";
chronic hepatitis with decompensated liver cirrhosis;
chronic hepatitis in patients receiving or who recently received immunosuppressants (except for short-term corticosteroid courses);
autoimmune hepatitis or history of autoimmune diseases; the drug is contraindicated in organ transplant recipients receiving immunosuppressants;
thyroid disorders, except when thyroid function is controlled by standard methods;
combination of Bioferon with telbivudine;
severe psychiatric disorders in history, especially severe depression, suicidal ideation, and suicide attempts.

Combination therapy with interferon alfa-2b/ribavirin should not be used:

in patients with creatinine clearance below 50 ml/min;
in pregnant women or male partners of pregnant women – in the presence of autoimmune hepatitis.

Consider safety information regarding ribavirin.

Interaction with other medicinal products and other forms of interaction.

When treating with Bioferon, narcotic, hypnotic, or sedative agents should be prescribed with caution. Interactions between Bioferon and other medicinal products have not been fully evaluated. Bioferon should also be used with caution in combination with myelosuppressive agents.

Interferons may affect oxidative metabolism processes; therefore, this should be considered when administering Bioferon concomitantly with drugs metabolized via this pathway (e.g., xanthine derivatives – theophylline and aminophylline). If concomitant therapy with xanthines is necessary, serum theophylline levels should be monitored so that the dose can be adjusted if needed.

In patients receiving interferon alfa, pulmonary infiltrates, pneumonitis, and pneumonia, sometimes fatal, have been rarely observed. The etiology is unknown, but adverse outcomes occurred more frequently in patients who concurrently received Sho-sai-ko-to, a Chinese herbal preparation. Administration of Bioferon with other chemotherapeutic agents may increase the risk of toxicity. Safety information regarding ribavirin should be considered when Bioferon is used in combination with ribavirin. Clinical trials investigating the combination of telbivudine with pegylated interferon alfa-2a indicate that this combination is associated with a higher risk of peripheral neuropathy. The mechanism is unknown. Furthermore, since the safety and efficacy of this combination for the treatment of chronic hepatitis B have not been established, the use of Bioferon in combination with telbivudine is contraindicated.

Additional information on the concomitant use of interferon alfa-2b and ribavirin is provided in the ribavirin product information leaflet.

Special precautions for use.

Interferon alfa-2b may cause or exacerbate neuropsychiatric, autoimmune, ischemic, and infectious disorders, which in some cases may be life-threatening. Therefore, careful clinical and laboratory monitoring of the patient is required during interferon therapy. The drug should be discontinued in cases of severe conditions or progression of symptoms. In many cases, although not always, symptoms resolve after discontinuation of the drug.

Interferon alfa-2b may cause bone marrow suppression and severe cytopenia; aplastic anemia is extremely rare. Therefore, blood cell counts should be monitored before and during therapy. The drug should be discontinued if neutrophil count falls below 0.5 × 10⁹/L or platelet count falls below 25 × 10⁹/L.

Central nervous system (CNS) adverse effects

Serious CNS complications, including depressive and suicidal conditions, may occur during interferon alfa-2b therapy. These effects may persist after therapy discontinuation, predominantly within a 6-month follow-up period. In children treated with interferon alfa-2b in combination with ribavirin, such complications occurred more frequently than in adults (including during the 6-month period after therapy completion). As in adult patients, other psychiatric adverse effects (depression, emotional lability, and somnolence) and other CNS reactions, including aggressive behavior (often directed toward others), bipolar disorders, mania, confusion, and changes in mental status, have been observed in children. Close monitoring is required to detect such adverse effects promptly. Upon their occurrence, the risk should be evaluated and appropriate therapy considered. If psychiatric symptoms worsen or suicidal behavior occurs, the drug should be discontinued and appropriate psychiatric treatment initiated.

Use in patients with psychiatric disorders or psychiatric history

If interferon alfa-2b treatment is considered necessary for adult patients with psychiatric disorders or psychiatric history, careful monitoring for any psychiatric symptoms is required. If such symptoms occur, the physician should consider their potential severity and the need for adequate treatment (see section "Contraindications"). Interferon alfa-2b is contraindicated in children with serious psychiatric disorders or psychiatric history.

Patients with substance dependence

During interferon alfa therapy in patients infected with hepatitis C virus who abuse alcohol, cannabis, etc., the risk of developing psychiatric disorders or worsening of pre-existing conditions increases. If interferon alfa-2b treatment is required for such patients, a multidisciplinary approach should be considered, including consultation with a mental health specialist or an addiction specialist, to evaluate the patient's condition, treatment, and ongoing monitoring. Close monitoring is required both during and after therapy completion.

Use in patients with chronic hepatitis C and B

Interferon alfa-2b should not be used in decompensated liver disease, autoimmune hepatitis, or autoimmune disorders in medical history. The drug should not be used in patients receiving immunosuppressive therapy after transplantation. Data indicate that interferon alfa-2b may worsen liver disease progression, cause jaundice, hepatic encephalopathy, liver failure, and may be fatal. The drug should be discontinued upon signs of liver failure.

In patients with chronic hepatitis B and impaired synthetic liver function, the risk of clinically decompensated states is increased. In such patients, monitoring of serum ALT activity, prothrombin time, alkaline phosphatase, albumin, and bilirubin levels is required. When prescribing interferon to such patients, the potential risk should be weighed against the potential benefit for each individual patient. Concomitant therapy with interferon alfa-2b and ribavirin is contraindicated in severe renal impairment due to the risk of hemolytic anemia, and careful monitoring is required in moderate renal impairment.

Children: growth and development (chronic hepatitis C)

During treatment courses with interferon (standard and pegylated)/combination therapy with ribavirin lasting up to 48 weeks in patients aged 3 to 17 years, weight loss and growth retardation were common. Data on longer-term treatment of children receiving combination therapy with standard interferon/ribavirin also indicate significant growth delays (a decrease in height percentile of >15 percentiles compared to baseline) in 21% of children, despite no treatment for more than 5 years.

Information on final adult height in 14 adults from these children 10–12 years after completion of interferon alfa-2b therapy indicated that 12 of them still exhibited growth deficit relative to percentiles <15.

Individual benefit/risk assessment in children

The expected benefit of treatment should be carefully weighed against safety data obtained from clinical trials in children.

The risk of reduced final adult height should be assessed considering the child's disease characteristics and expected treatment response:

It should be noted that combination therapy causes growth suppression, and reversibility of this process is questionable.
The degree of risk should be assessed considering disease progression symptoms (especially fibrosis), comorbidities that may negatively affect disease course (e.g., HIV infection), and prognostic factors for response (genotype and viral load).

As soon as possible, treatment should be administered after the pubertal growth spurt to minimize the risk of growth suppression. There are no data on long-term effects on sexual maturation.

Hypersensitivity reactions

Acute hypersensitivity reactions (urticaria, angioedema, bronchospasm, anaphylaxis) during interferon alfa-2b use are rare. Upon occurrence of such reactions, therapy should be immediately discontinued and appropriate medical measures taken. Transient rash is not a reason to discontinue therapy.

If liver function disorders develop during treatment with Bioferon, the patient's condition should be monitored, and the drug should be discontinued if symptoms progress.

Liver function changes

In some cases, hepatotoxicity manifestations have been observed during interferon alfa-2b use.

Any patient who develops liver function disorders during Bioferon treatment should be closely monitored, and therapy should be discontinued if signs and symptoms persist or progress. Bioferon increases the risk of liver decompensation and fatal outcome in patients with liver cirrhosis. Patients with chronic hepatitis and prolonged prothrombin time or other coagulation disorders should discontinue Bioferon treatment. Fatal cases due to hepatotoxicity have been observed in patients receiving interferon alfa. Moderate and severe adverse reactions may require dose adjustment. In some cases, discontinuation of Bioferon treatment may be necessary. Although such cases have been more frequently reported in patients with chronic hepatitis C receiving interferon alfa, they have also occurred in cancer patients receiving interferon alfa.

Pyrexia

Fever may be associated with flu-like syndrome; however, other possible causes of fever should be ruled out if fever persists.

Patients with psoriasis and sarcoidosis

Since interferon alfa-2b may worsen pre-existing psoriasis and sarcoidosis, prescribing Bioferon to such patients is recommended only if the potential benefit justifies the potential risk.

Patients with pre-existing cardiac disorders

Bioferon should be prescribed with caution in patients with a history of cardiovascular diseases. Continuous monitoring is required for adult patients with a history or clinical evidence of congestive heart failure, myocardial infarction, or arrhythmia (see section "Contraindications"). Cardiovascular events, including hypotension, arrhythmia, or tachycardia (more than 150 beats/min), may occur during interferon alfa-2b use. Cardiomyopathy and myocardial infarction have been rarely reported. In some cases, these events occurred in patients without a history of cardiovascular pathology. Cases of cardiomyopathy have been reported during treatment of AIDS-associated Kaposi's sarcoma in patients receiving recombinant interferon alfa-2b. Hypotension may develop within 2 days after interferon alfa-2b administration, which may require supportive therapy, including infusion therapy to maintain blood volume. Supraventricular arrhythmia has been rarely observed, likely associated with pre-existing pathology and prior use of cardiotoxic agents. Dose adjustment, specific therapy, or therapy discontinuation may be required upon occurrence of these events.

Hypotension

Hypotension may occur during Bioferon treatment, which may require supportive therapy, including infusion therapy to maintain intravascular volume.

Need for adequate hydration

Hypotension due to dehydration has been observed in some patients receiving interferon alfa-2b. Adequate hydration should be maintained. In case of hypotension, infusion therapy is required.

Patients with severe diseases

Bioferon should be prescribed with caution to patients with severe diseases, such as lung diseases in history (e.g., chronic obstructive pulmonary disease), and diabetes with risk of ketoacidosis. Caution is required when prescribing interferon alfa-2b to patients with coagulation disorders (thrombophlebitis, pulmonary embolism) and pronounced myelosuppressive conditions.

Pulmonary pathologies

Rarely, interferon alfa-2b use is associated with lung infiltrates, pneumonitis, and pneumonia development, sometimes with fatal outcome. The causes of such complications remain unclear. However, these manifestations were more frequently observed in patients with chronic hepatitis C, oncological diseases, and in patients who concurrently received Sho-sai-ko-to (sho-saiko-to) (a Chinese herbal preparation) with interferon alfa (see section "Interaction with other medicinal products and other forms of interaction"). Patients developing cough, breathing difficulties, fever, or any other respiratory symptoms should undergo chest X-ray. Close monitoring is required for patients with lung infiltrates or other lung function disorders. If necessary, interferon alfa-2b should be discontinued.

Rapid discontinuation of interferon alfa and corticosteroid therapy likely leads to rapid resolution of pulmonary adverse effects.

Autoantibodies and autoimmune changes

Autoimmune conditions may develop during interferon alfa-2b therapy. Patients predisposed to autoimmune changes may have a higher risk; however, no reduction in interferon biological activity has been reported in these cases. Close monitoring and risk/benefit assessment for continuing interferon therapy are required in such cases.

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported among patients with chronic hepatitis C receiving interferon alfa. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory organs, meninges, and skin. Upon suspicion of VKH, antiviral therapy should be discontinued, and the need for corticosteroid therapy evaluated.

Carbohydrate metabolism disorders

Rarely, diabetes mellitus and hyperglycemia have been observed in patients receiving recombinant interferon alfa-2b injections. Patients with symptoms should monitor blood glucose levels and undergo appropriate monitoring. Diabetic patients may require adjustment of antidiabetic diet.

Hypertriglyceridemia

High triglyceride levels have been observed in patients receiving interferon, requiring clinical management. In some cases, interferon use may increase triglyceride levels, potentially leading to pancreatitis. Bioferon use should be discontinued if triglyceride levels persist above 1000 mg/dL and pancreatitis symptoms (abdominal pain, nausea, vomiting) are present.

Thyroid disorders

Rarely, thyroid abnormalities (hypo- or hyperthyroidism) may develop during interferon alfa-2b use, the mechanism of which remains unknown. Bioferon is not indicated if thyroid dysfunction cannot be controlled with medication. TSH levels in blood should be checked before prescribing the drug. Appropriate investigations and treatment should be initiated upon thyroid dysfunction during therapy. If thyroid function cannot be normalized, the drug should be discontinued. In some cases, such thyroid disorders do not resolve after Bioferon discontinuation.

Myelosuppression

Interferon alfa-2b therapy causes myelosuppression, leading to severe cytopenia, including rare cases of aplastic anemia. Complete blood count is recommended before therapy initiation and regular monitoring during therapy. Bioferon treatment should be discontinued in patients with neutrophil count <0.5 × 10⁹/L or platelet count <25 × 10⁹/L.

Vision disorders

Interferon alfa-2b or other interferon alfa therapy may cause or exacerbate vision disturbances, including vision loss, retinopathy (including macular edema), retinal vein or artery thrombosis, retinal hemorrhages, cotton-wool spots, optic neuritis, and optic disc edema. Ophthalmological examination is required before interferon alfa-2b prescription. Periodic ophthalmological examinations are required during therapy in patients with pre-existing conditions (e.g., diabetic or hypertensive retinopathy), and drug use should be discontinued upon ophthalmological symptoms or worsening of pre-existing conditions.

Consciousness disorders and encephalopathy

Some patients experienced mental sluggishness, significant confusion, and coma, including encephalopathy cases, especially in elderly patients receiving high doses. Generally, these events are reversible, although recovery may take up to three weeks in some cases. Seizures have been extremely rarely associated with interferon alfa-2b use.

Rejection of transplanted kidneys and liver

Available data suggest that interferon alfa therapy may be associated with increased frequency of kidney transplant rejection. Liver transplant rejection has also been reported.

Chronic hepatitis C.

Combination therapy with ribavirin.

To determine whether confirmatory liver biopsy is required, agreement with current treatment protocols is necessary before initiating interferon alfa and ribavirin therapy. Some patients with genotypes 2 and 3 may start treatment without histological confirmation.

Monotherapy.

In adults receiving interferon alfa-2b, rare cases of thyroid changes, such as hypothyroidism and hyperthyroidism, have been observed. In clinical trials with interferon alfa-2b, thyroid dysfunction occurred in 2.8% of patients (see "Thyroid disorders" section under "Special precautions for use").

Additional thyroid monitoring, especially in children

Elevated TSH levels were observed in approximately 12% of children receiving interferon alfa-2b and ribavirin combination therapy. Another 4% demonstrated temporary normalization to normal levels. TSH levels and any thyroid changes should be evaluated and treated if necessary before initiating Bioferon therapy. Treatment may be initiated if TSH levels can be maintained within normal range with medication. Pediatric patients with signs of thyroid dysfunction should be examined every 3 months.

Patients with hepatitis C/hepatitis B virus co-infection ( HCV/HBV)

Cases of hepatitis B reactivation (some with severe outcomes) have been reported during interferon alfa use in patients co-infected with HCV and HBV. The frequency of this reactivation phenomenon is likely low. Before initiating hepatitis C treatment with Bioferon, all patients should be screened for hepatitis B. Treatment should be discontinued in patients developing signs or symptoms of liver failure. Patients with chronic hepatitis B and signs of reduced liver function may demonstrate a high risk of clinical decompensation if aminotransferase levels increase during Bioferon therapy. These patients should be closely monitored, including strict monitoring of clinical symptoms and liver function tests (ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin) if ALT levels increase due to chronic hepatitis B during Bioferon therapy. Potential risks versus expected benefits of treatment should be evaluated before initiating Bioferon therapy in these patients. Combination therapy with Bioferon and ribavirin has been associated with hemolytic anemia. Combination therapy with Bioferon and ribavirin is not recommended in patients with severe renal impairment and should be prescribed with caution in patients with moderate renal impairment.

Use in AIDS patients

In patients co-infected with HIV and hepatitis receiving highly active antiretroviral therapy (HAART), the risk of lactic acidosis is high. Therefore, additional interferon alfa-2b with ribavirin should be prescribed with caution (consider ribavirin safety information). In co-infected patients with liver cirrhosis receiving HAART, the risk of liver failure and fatal outcome is high. Concomitant use of interferon alfa-2b and zidovudine may have a synergistic effect on neutropenia development. Careful monitoring of blood counts is recommended when prescribing Bioferon to patients with myelosuppression or receiving myelosuppressive agents.

Concomitant chemotherapy

Interferon alfa-2b use with chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased cumulative toxicity, including severe and even fatal cases. Serious life-threatening or fatal adverse effects, such as mucositis, diarrhea, neutropenia, renal failure, and electrolyte imbalance, may be intensified. Dose adjustment of Bioferon and concomitant chemotherapeutic agents is required due to increased toxicity risk. Skin vasculitis frequency and severity may increase when interferon alfa-2b is used with hydroxyurea.

Dental and periodontal diseases

Data indicate that patients receiving concomitant interferon alfa-2b and ribavirin therapy may develop dental and periodontal diseases, potentially leading to tooth loss. Dry mouth, occurring during prolonged Bioferon and ribavirin use, negatively affects teeth and oral mucosa condition. Careful twice-daily tooth brushing and regular dental check-ups are recommended. Vomiting may occur as an adverse effect during interferon with ribavirin therapy. In case of vomiting episodes, thorough mouth rinsing is required.

Flu-like reactions and other systemic effects

These adverse effects occur most frequently (in 90% of patients), usually during initial doses. Fever is usually associated with flu-like syndrome; however, if fever persists, other causes should be ruled out. Weight loss was also observed during initial interferon doses. Muscle cramps and musculoskeletal problems occur in approximately 45% of patients.

Neurosensory disorders

Taste, vision, hearing, and smell changes have been reported, not requiring therapy interruption.

Effect of the drug on laboratory parameters

Standard hematological parameters and blood biochemistry, including electrolyte balance, liver enzymes, serum proteins, bilirubin, and serum creatinine, should be monitored before Bioferon prescription and periodically during therapy.

In patients with hepatitis B and C, testing is recommended at weeks 1, 2, 4, 8, 12, and 16 of therapy, and thereafter every two months. If serum alanine aminotransferase activity increases twofold compared to baseline, Bioferon therapy may continue in the absence of symptoms indicating liver dysfunction. Other tests, including prothrombin time, alkaline phosphatase activity, albumin, and bilirubin (every two weeks), should also be performed. Electrocardiographic examination is required before therapy initiation and during therapy in patients with pre-existing cardiovascular diseases and severe oncological conditions.

Moderate leukopenia and increased liver enzyme activity may occur with direct interferon alfa-2b injection into the affected area; therefore, monitoring of these parameters is recommended. Chest X-ray is required if clinically indicated. In patients with malignant melanoma, blood counts and liver enzyme activity should be monitored (weekly during induction therapy and monthly during maintenance therapy). Liver function tests (ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin) should be monitored every two weeks if ALT levels increase.

Carcinogenicity, mutagenicity, effects on fertility

Bioferon has not shown carcinogenic properties. Interferon is known to reduce fertility. Interferon alfa affects the menstrual cycle. Decreased serum estradiol and progesterone levels have been observed in women receiving leukocyte interferon. Therefore, effective contraception methods are recommended for women during Bioferon use. Bioferon should be used with caution in fertile men.

Interferon alfa-2b has not shown mutagenic properties in studies.

Use in patients aged 65 years and older

Bioferon should be used with caution in these patients due to decreased liver and kidney function, reduced hematopoiesis efficiency, and presence of comorbidities and concomitant therapies. The risk of adverse reactions is particularly high with renal function impairment, as Bioferon is primarily excreted by kidneys. Bioferon use in patients aged 65 years and older requires monitoring of kidney function, and dose adjustment should be considered based on symptoms and laboratory results.

Human albumin

The drug contains human albumin. Due to rigorous donor blood screening during production, the risk of viral disease transmission is extremely low. The risk of Creutzfeldt-Jakob disease agent transmission is also considered extremely low. No cases of viral infection transmission with Bioferon use have been registered.

Information for patients

Patients should be informed about the following:

Seek medical help if symptoms indicating severe adverse reactions occur. Severe adverse reactions include depressive state (suicide attempts), cardiovascular events, vision worsening or loss indicating ophthalmological toxicity, pancreatitis or colitis (accompanied by severe abdominal pain), cytopenia (with persistent fever, bleeding, breathing difficulties);
Some adverse reactions (increased fatigue, reduced attention concentration) may affect the ability to perform certain activities;
Bioferon use in combination with ribavirin is associated with increased risk of fetal developmental abnormalities; therefore, women and men should use contraception during therapy and for 6 months after therapy completion;
Dehydration should be avoided at the beginning of therapy. Antipyretics should be used if flu-like symptoms develop.

Information on sodium compounds.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Women of reproductive age / Contraception in men and women

Women of reproductive age should use effective contraception methods during therapy. Decreased serum estradiol and progesterone levels have been reported in women receiving human leukocyte interferon. Bioferon should be used with caution in fertile men. Effective contraception methods are recommended for men undergoing interferon alfa therapy and their female partners of reproductive age.

Use during pregnancy. Category C (according to FDA recommendations: animal studies showed teratogenic or embryotoxic effects of drugs on the fetus, but controlled studies involving humans were not conducted)

Experimental animal studies showed that recombinant interferon alfa-2b administration induces abortions in pregnant monkeys at doses of 18 and 30 million IU/kg (equivalent to human doses of 5 and 10 million IU/kg, based on adult human body surface area of 60 kg). Adequate controlled studies in pregnant women have not been conducted. However, Bioferon may be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use during pregnancy. Category X (according to FDA recommendations: animal and human studies revealed obvious danger to the fetus associated with high risk of congenital abnormalities or persistent fetal damage)

This section applies only to combination therapy with ribavirin (consider ribavirin safety information). Ribavirin has teratogenic effects; therefore, combination therapy with interferon alfa-2b and ribavirin is contraindicated during pregnancy.

Use in breastfeeding women

It is unknown whether the drug penetrates into human breast milk. In mouse studies, interferon alfa-2b presence in milk after injection into the body has been proven. Therefore, if interferon use in breastfeeding women is absolutely necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving vehicles or operating machinery.

Fatigue and somnolence may occur during Bioferon use. Therefore, individuals taking this drug should refrain from driving vehicles and operating high-risk machinery.

Administration and Dosage

The drug should be administered subcutaneously, intramuscularly, or intravenously. The solvent is water for injections. When dissolving, mix the powder with water by gently rotating the vial; do not shake.

After reconstitution, the vial with Bioferon solution must be used within two hours if stored at room temperature, or within 24 hours if stored in a refrigerator. The drug does not contain stabilizers; therefore, more than one dose should not be withdrawn from the vial to prevent contamination. Discard any unused portion of the solution!

Subcutaneous, intramuscular, and lesion-site administration

Reconstitute the contents of the vial in 1 mL of water for injections. Draw the required dose into a syringe. The solution should not contain particles of undissolved material.

Intravenous infusion

The infusion solution should be prepared immediately before use. Reconstitute the contents of the vial in 1 mL of water for injections, gently swirling the vial until the powder is completely dissolved. Add the required amount of solution to 100 mL of isotonic sodium chloride solution for infusion. The final concentration of interferon alfa-2b in the infusion solution should be no less than 10 million IU/100 mL.

Chronic Hepatitis B

For adults: The recommended dose of interferon alfa-2b for the treatment of chronic hepatitis B is 30–35 million IU weekly administered subcutaneously or intramuscularly (either 5 million IU daily or 10 million IU three times weekly) for 4 months.

For children aged 1 year and older: The recommended dose of interferon alfa-2b for the treatment of chronic hepatitis B is 3 million IU/m² three times weekly for the first week, increased to 6 million IU/m² three times weekly (maximum 10 million IU three times weekly) administered subcutaneously for 16–24 weeks.

Dose adjustment. In case of pronounced adverse reactions or laboratory abnormalities during Bioferon therapy, the dose should be reduced by 50% or treatment temporarily discontinued until adverse effects resolve. If intolerance persists even after dose reduction, treatment should be discontinued.

In the presence of hematological abnormalities, the dose should be reduced by 50% under the following conditions: total leukocyte count below 1.5 × 10⁹/L, granulocyte count below 0.75 × 10⁹/L, or platelet count below 50 × 10⁹/L. Treatment should be discontinued if total leukocyte count falls below 1.0 × 10⁹/L, granulocyte count below 0.5 × 10⁹/L, or platelet count below 25 × 10⁹/L. After normalization of hematological parameters, therapy with Bioferon may be continued at the initial dose. If no improvement (based on serum HBV DNA levels) is observed after 3–4 months of treatment at the maximum tolerated dose, Bioferon should be discontinued.

Treatment with Bioferon leads to viral remission (absence of HBeAg in serum) and normalization of serum ALT levels.

Prior to initiating Bioferon therapy, liver biopsy is recommended to assess the extent of liver damage. It is also necessary to determine whether liver disease is compensated. Clinical signs of compensated liver disease include:

Absence of encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation;
Normal bilirubin levels;
Stable serum albumin levels within normal range;
Prolongation of prothrombin time no more than 3 seconds in adults, no more than 2 seconds in children;
Leukocyte count not less than 4000/mm³;
Platelet count not less than 100,000/mm³ in adults and not less than 150,000/mm³ in children.

Interferon alfa-2b should not be used in chronic hepatitis not caused by hepatitis B or C virus.

Prior to initiating Bioferon therapy, a complete blood count including platelet count should be performed to monitor drug toxicity during treatment. These tests should be repeated at 1, 2, 4, 8, 12, and 16 weeks. At the same time points, liver function tests (serum ALT, albumin, and bilirubin) should be performed. HBeAg, HBsAg, and ALT should be assessed at the end of therapy and at 3 and 6 months thereafter, as virological response may occur up to 6 months after completion of treatment.

Chronic Hepatitis C

In adults, Bioferon is administered subcutaneously or intramuscularly at a dose of 3 million IU three times weekly as monotherapy or in combination with ribavirin. If the drug is well tolerated and ALT levels normalize within 16 weeks of starting treatment, therapy should continue on the same regimen for 18–24 months.

If ALT normalization does not occur within 16 weeks of starting treatment, the likelihood of a positive response with continued therapy is low. In such cases, further use of Bioferon is not recommended.

In children aged 3 years and older, Bioferon is administered subcutaneously at a dose of 3 million IU/m² three times weekly in combination with ribavirin in capsules or oral solution (daily dose of ribavirin divided into two doses, taken morning and evening with food).

In adults with relapse, Bioferon is used in combination with ribavirin for 6 months.

Treatment-naïve patients:

In adults, the efficacy of Bioferon is enhanced when used concomitantly with ribavirin. Monotherapy with Bioferon should be used only in cases of ribavirin intolerance or contraindications. Combination therapy (Bioferon and ribavirin) is recommended for at least 6 months. For patients with genotype 1 and high viral load, if HCV RNA remains positive after 6 months of treatment, therapy should be extended for another 6 months (total treatment duration of 1 year). When deciding on extending therapy to 12 months, other negative prognostic factors should also be considered (age over 40 years, male sex, presence of fibrosis).

When Bioferon is used as monotherapy, the optimal duration of treatment has not been definitively established; therapy for 12–18 months is recommended. HCV RNA should be assessed 3–4 months after starting treatment, and therapy should be continued if the result is negative.

In children, for children who have not previously received Bioferon for chronic hepatitis C, the following regimen is recommended (in combination with ribavirin):

Genotype 1: Recommended treatment duration is 1 year. If no virological response is observed within 3 months of starting therapy, continuation of treatment is not recommended (negative predictive value 96%). Virological response is defined as absence of HCV RNA 3 months after initiation of therapy;
Genotype 2/3: Recommended treatment duration is 6 months.

The proportion of patients with undetectable HCV RNA 1 year after completing 6 months of follow-up is 36% for genotype 1 and 81% for genotypes 2/3/4.

To confirm the diagnosis of chronic hepatitis, liver biopsy and testing for anti-HCV antibodies should be performed. Interferon alfa-2b should not be used in chronic hepatitis of non-viral etiology, such as autoimmune hepatitis. Before initiating treatment, it must be confirmed that liver disease is compensated. To initiate Bioferon therapy, patients with chronic hepatitis C must meet the following criteria:

Absence of encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation;
Serum bilirubin level not exceeding 2 mg/dL;
Stable serum albumin level within normal range;
Prolongation of prothrombin time no more than 3 seconds;
Leukocyte count not less than 3000/mm³;
Platelet count not less than 70,000/mm³;
Normal or near-normal serum creatinine level.

Prior to initiating Bioferon therapy, a complete blood count including platelet count should be performed to monitor drug toxicity during treatment. These tests should be repeated at 1 and 2 weeks after starting therapy, then monthly. Serum ALT activity should be assessed approximately every 3 months to evaluate response to therapy.

Bioferon may be prescribed in patients with thyroid abnormalities if concomitant medications maintain TSH levels within normal range. TSH levels should be within normal range before starting therapy; TSH should be retested at 3 and 6 months.

Hairy Cell Leukemia

Recommended dose: 2 million IU/m² three times weekly administered intramuscularly or subcutaneously for 6 months, with or without splenectomy. The drug should not be administered intramuscularly if platelet count is below 50 × 10⁹/L. In most patients, normalization of one or more hematological parameters occurs within 1–2 months of starting treatment. Normalization of all three hematological parameters (granulocytes, platelets, and hemoglobin) may require 6 or more months.

Dose adjustment. In case of pronounced adverse reactions during Bioferon therapy, the dose should be reduced by 50% or treatment temporarily discontinued until adverse effects subside. Therapy may then be resumed at 50% of the initial dose (1 million IU/m²). If intolerance persists even after dose reduction, treatment should be discontinued. Bioferon therapy should be discontinued if no response is observed after 6 months of treatment.

Chronic Myeloid Leukemia

Recommended dose: 4–5 million IU/m² subcutaneously daily. In some cases, treatment efficacy is enhanced by combination therapy with Bioferon (5 million IU/m² once daily subcutaneously) and cytarabine (Ara-C) at 20 mg/m² subcutaneously for 10 days per month (maximum daily dose 40 mg). After normalization of leukocyte count, maintenance of hematological remission requires continued use of the maximum tolerated dose of Bioferon (4–5 million IU/m² once daily subcutaneously). If no partial hematological remission is achieved within 8–12 weeks, treatment should be discontinued.

Most patients show significant hematological and cytogenetic responses after such treatment. A response is considered major if the proportion of Ph+ cells in bone marrow falls below 34%; minor if Ph+ cells range from 34% to 90%.

Multiple Myeloma

In patients who have reached the plateau phase (more than 50% reduction in myeloma protein), maintenance therapy with Bioferon is administered subcutaneously at 3 million IU/m² three times weekly following initial induction chemotherapy.

Follicular Lymphoma

Recommended dose: 5 million IU subcutaneously three times weekly for 18 months in combination with anthracycline-based chemotherapy.

Dose adjustment:

When adding interferon alfa to combination therapy, the dose of myelosuppressive agents should be reduced by 25% compared to the full dose specified in the CHOP regimen, and the treatment cycle duration should be extended by 33% (e.g., from 21 to 28 days);
If neutrophil count falls below 1500/mm³ or platelet count below 75,000/mm³, the next chemotherapy cycle should be delayed;
If serum AST activity exceeds the upper limit of normal by fivefold or serum creatinine exceeds 2.0 mg/dL, Bioferon should be discontinued;
Bioferon should be discontinued if neutrophil count falls below 1000/mm³ or platelet count below 50,000/mm³;
If neutrophil count is above 1000/mm³ but below 1.5 × 10⁹/L, the dose of Bioferon should be reduced by 50% (2.5 million IU three times weekly). The dose may be increased back to the initial level (5 million IU three times weekly) only after neutrophil count exceeds 1.5 × 10⁹/L.

Carcinoid Tumors

Initial dose: 5 million IU (range 3–9 million IU) subcutaneously three times weekly. In progressive disease, the dose may be increased to 5 million IU daily. Bioferon should be discontinued during the perioperative period. Treatment may continue as long as a clinical response to interferon alfa-2b is maintained.

Malignant Melanoma

For induction therapy, Bioferon is administered at 20 million IU/m² intravenously five times weekly for 4 weeks. The drug is infused after dilution in isotonic sodium chloride solution over 20 minutes.

For maintenance therapy, the recommended dose is 10 million IU/m² subcutaneously three times weekly for 48 weeks.

In case of severe adverse effects, particularly granulocyte count < 500/mm³ or serum alanine aminotransferase activity exceeding fivefold the upper limit of normal, treatment should be temporarily discontinued until adverse effects resolve. Afterward, the drug may be resumed at a dose reduced by 50%. If intolerance persists even after dose reduction, or if granulocyte count falls below 250/mm³ or serum ALT/AST exceeds tenfold the upper limit of normal, the drug should be discontinued.

Genital Warts (Condyloma Acuminatum)

The drug is administered locally into the lesion area. Recommended dose: 1 million IU per wart (no more than 5 warts per treatment course). Administration is performed into the base of the wart three times weekly on alternate days for 3 weeks. An additional course may be administered at 12–16 weeks.

Dose adjustment is not required.

Administration technique. Use a tuberculin syringe with a 25–30 gauge needle. Inject the drug toward the center of the base of the wart, almost parallel to the skin surface (similar to a tuberculin skin test). This ensures interferon reaches the core of the lesion and infiltrates it, causing a local reaction. Care must be taken not to inject too deeply. The drug should not be administered subcutaneously beneath the base of the wart. However, insufficient depth of injection will result in infiltration of only the keratinized layer, not the dermal core of the wart.

Kaposi's Sarcoma Associated with AIDS

Recommended dose of Bioferon: 30 million IU/m² subcutaneously or intravenously three times weekly until maximum response is achieved, up to 16 weeks. Dose reduction is frequently required during therapy.

Dose adjustment:

In case of serious adverse reactions, therapy should be suspended or the dose of Bioferon reduced by 50%;
After resolution of adverse reactions, treatment may be continued at the reduced dose;
If adverse reactions recur at the reduced dose, the drug should be discontinued.

Children

The safety and efficacy of interferon alfa-2b in children have not been established, except in the following cases:

In chronic hepatitis B, safety and efficacy have been established for patients aged 1–17 years (see sections "Indications" and "Administration and Dosage"). Safety and efficacy of interferon alfa-2b in children under 1 year of age with chronic hepatitis B have not been established;
Bioferon in combination with ribavirin is indicated for treatment of children aged 3 years and older with chronic hepatitis C, provided liver disease is compensated, no prior therapy has been administered, and HCV RNA is detectable in serum.

Overdose

Limited information is available on cases of interferon alfa-2b overdose. Typically, the primary effects of overdose are similar to those observed with therapeutic doses. Symptoms described include liver enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction. No toxic effects are observed after oral ingestion of interferon alfa-2b, as it is practically not absorbed into the bloodstream following oral administration.

There is no specific antidote for interferon alfa-2b overdose. Hemodialysis and peritoneal dialysis are poorly effective in cases of interferon alfa-2b overdose.

Treatment is symptomatic.

Adverse Reactions

Most adverse reactions, except for the influenza-like syndrome (manifested as fever, fatigue, headache, myalgia), are dose-dependent. They are usually mild or moderate in severity at doses below 10 million IU per day.

Decreased arterial pressure frequently occurs with systemic administration but rarely causes subjective symptoms; arterial hypotension may develop during or within two days after treatment, sometimes requiring supportive therapy, including infusion therapy, to maintain circulating blood volume. Hypertension may occasionally occur, typically mild and transient.

During therapy with interferon alfa-2b, neutralizing antibodies may develop (consider safety information regarding ribavirin concerning unpredictable effects when used in combination with Bioferon).

Aplastic anemia is extremely rare during treatment with interferon alfa-2b (monotherapy or in combination with ribavirin).

Cardiovascular adverse events, primarily arrhythmias, occur more frequently in patients with pre-existing cardiovascular disease or prior use of cardiotoxic drugs. Rarely, cardiomyopathy may develop, which is reversible in patients without prior signs of heart disease upon temporary discontinuation of interferon alfa.

A broad spectrum of autoimmune and immune-mediated changes has been reported during treatment with alpha-interferons, including thyroid dysfunction, systemic lupus erythematosus, rheumatoid arthritis (new onset or exacerbation), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, and neuropathies, including mononeuropathies.

Hypersensitivity reactions, including urticaria, angioedema, bronchospasm, and anaphylaxis, are rarely observed during interferon alfa-2b administration.

Laboratory abnormalities that may have clinical significance are more likely at interferon alfa-2b doses exceeding 10 million IU per day. These may include leukopenia, erythropenia, thrombocytopenia, decreased hemoglobin levels, increased alkaline phosphatase and lactate dehydrogenase (LDH) activity, increased serum creatinine and blood urea nitrogen. Elevated ALT/AST levels may occur in some patients without hepatitis, as well as in patients with chronic hepatitis B, coinciding with viral DNA clearance.

The adverse reactions listed below were reported during clinical trials and in the post-marketing period. Frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and unknown (frequency cannot be estimated from available data).

Within each category, adverse reactions are listed in decreasing order of severity.

Adverse Reactions with Bioferon

Very Common

Infections and infestations: viral infections*, pharyngitis*;

Metabolism and nutrition disorders: anorexia;

Psychiatric disorders: depression, insomnia, anxiety, impaired mental orientation, agitation, emotional lability*;

Nervous system disorders: dizziness, headache, decreased concentration, dry mouth;

Respiratory, thoracic and mediastinal disorders: dyspnea, breathing difficulty, cough*;

Eye disorders: blurred vision;

Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain, stomatitis, dyspepsia;

Skin and subcutaneous tissue disorders: alopecia, pruritus, dry skin, rash;

Musculoskeletal and connective tissue disorders: myalgia, arthralgia, muscle and bone pain;

General disorders and administration site conditions: injection site inflammation, injection site reaction, irritability, chest pain, influenza-like symptoms, asthenia, weakness, fever, chills;

Investigations: weight loss.

Common

Infections and infestations: treatment-resistant herpes virus infection;

Metabolism and nutrition disorders: hyperuricemia, hypocalcemia, thirst, dehydration;

Psychiatric disorders: excitement, nervousness, sleep disturbances, decreased libido;

Nervous system disorders: increased sweating, hypoesthesia, confusion, paresthesia, tremor, migraine, lacrimation disorder, skin redness, somnolence, taste perversion;

Respiratory, thoracic and mediastinal disorders: bronchitis, non-productive cough, epistaxis, nasal congestion, rhinitis, common cold, sinusitis, breathing difficulty;

Gastrointestinal disorders: constipation, dehydration, gingivitis, glossitis, loose stools, ulcerative stomatitis, right upper quadrant abdominal pain;

Skin and subcutaneous tissue disorders: eczema, psoriasis (recurrence or exacerbation of pre-existing condition), erythematous rash, maculopapular rash, erythema;

Musculoskeletal and connective tissue disorders: arthritis;

General disorders and administration site conditions: general deterioration in health, injection site pain, injection site reactions;

Cardiovascular disorders: palpitations, tachycardia, hypertension;

Blood and lymphatic system disorders: thrombocytopenia, neutropenia, lymphadenopathy, lymphopenia, anemia;

Endocrine disorders: hyperthyroidism§, hypothyroidism§;

Eye disorders: blurred vision, conjunctivitis, eye pain, visual disturbances;

Ear and labyrinth disorders: vertigo, tinnitus;

Hepatobiliary disorders: hepatomegaly;

Renal and urinary disorders: frequent urination;

Reproductive system and breast disorders: amenorrhea, breast pain, menstrual disorder, dysmenorrhea, menorrhagia, vaginal disorders, vaginal pathology.

Uncommon

Infections and infestations: bacterial infections;

Nervous system disorders: peripheral neuropathy;

Cardiovascular disorders: pericarditis.

Rare

Infections and infestations: sepsis;

Psychiatric disorders: suicidal ideation;

Eye disorders: retinal hemorrhage§, retinopathy (including macular edema), obstruction of retinal arteries or veins§, visual acuity or visual field disturbances, optic neuritis, papilledema, white spots;

Respiratory, thoracic and mediastinal disorders: pneumonia.

Cardiovascular disorders: cardiomyopathy.

Very Rare

Immune system disorders: development or exacerbation of sarcoidosis;

Endocrine disorders: development or exacerbation of diabetes mellitus;

Metabolism and nutrition disorders: hyperglycemia, hypertriglyceridemia §, increased appetite;

Psychiatric disorders: suicide, suicide attempt, aggressive behavior (sometimes directed toward others), psychosis including hallucinations, homicidal ideation, altered mental status, mania, bipolar disorders;

Nervous system disorders: altered consciousness, neuropathy, polyneuropathy, seizures, encephalopathy, cerebral ischemia, intracranial hemorrhage, crisis;

Ear and labyrinth disorders: hearing impairment or loss;

Cardiovascular disorders: myocardial ischemia, myocardial infarction, hypotension§, peripheral ischemia;

Respiratory, thoracic and mediastinal disorders: pulmonary infiltration§, pneumonitis§;

Gastrointestinal disorders: pancreatitis, increased appetite, gum bleeding, colitis, primarily ulcerative and ischemic;

Hepatobiliary disorders: hepatotoxicity, which may lead to fatal outcome;

Skin and subcutaneous tissue disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis;

Musculoskeletal and connective tissue disorders: rhabdomyolysis (sometimes severe), leg cramps, back pain, myositis;

Renal and urinary disorders: nephrotic syndrome, renal failure;

Blood and lymphatic system disorders: aplastic anemia;

General disorders and administration site conditions: necrosis at injection site, facial swelling.

Frequency Not Known

Infections and infestations: reactivation of hepatitis B in patients co-infected with hepatitis C virus/hepatitis B virus (HCV/HBV);

Blood and lymphatic system disorders: pure red cell aplasia of bone marrow, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura;

Immune system disorders: systemic lupus erythematosus, vasculitis, rheumatoid arthritis (new onset or exacerbation), Vogt-Koyanagi-Harada syndrome, acute hypersensitivity reactions, including urticaria, angioedema, bronchospasm, anaphylaxis§;

Cardiovascular disorders: congestive heart failure, pericardial effusion, arrhythmias;

Respiratory, thoracic and mediastinal disorders: pulmonary fibrosis, pulmonary arterial hypertension #;

Gastrointestinal disorders: unspecified periodontal disorder, unspecified dental disorder §, tongue pigmentation;

Nervous system disorders: mononeuropathy, coma§;

Eye disorders: serous retinal detachment.

* These reactions occurred only during monotherapy with interferon alfa.

§ See section "Special Warnings and Precautions for Use".

Based on instructions for medical use of interferon-containing products.

Clinically significant laboratory abnormalities occurring more frequently at doses exceeding 10 million IU per day include decreased granulocyte and leukocyte counts; decreased hemoglobin and platelet counts; increased alkaline phosphatase, lactate dehydrogenase (LDG), serum creatinine, and serum urea nitrogen levels. Increased serum ALT/AST (serum glutamic pyruvic transaminase (SGPT)/serum glutamic oxaloacetic transaminase (SGOT)) levels have been observed in some patients without hepatitis, as well as in some patients with chronic hepatitis B during reduction of viral DNA load.

Adverse Reactions in Children

The overall spectrum of adverse reactions in children is similar to that in adults. Specific reactions include growth retardation and weight loss. Suicidal thoughts and behaviors occur more frequently in children during and within the six-month period following treatment compared to adult patients. As in adults, depression, emotional lability, and somnolence may occur in children. Fever, anorexia, vomiting, and injection site reactions are more commonly observed in children than in adults. Dose adjustments due to anemia and neutropenia are more frequently required in children.

Adverse Reactions Observed in Children

Very Common

Infections and infestations: viral infections, pharyngitis;

Blood and lymphatic system disorders: anemia, neutropenia;

Endocrine disorders: hypothyroidism§;

Psychiatric disorders: depression, emotional lability, insomnia;

Nervous system disorders: headache, dizziness;

Metabolism and nutrition disorders: anorexia;

Gastrointestinal disorders: abdominal pain, diarrhea, nausea, vomiting;

Skin and subcutaneous tissue disorders: alopecia, rash;

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, muscle and bone pain;

General disorders and administration site conditions: injection site inflammation, allergic reaction at injection site, injection site reactions, fatigue, chills, fever, influenza-like symptoms, malaise, irritability.

Investigations: decreased growth index (reduced growth and/or body weight relative to age)§.

Common

Infections and infestations: fungal infections, bacterial infections, dental abscess, herpes simplex, otitis media, pulmonary infection, urinary tract infection, vaginitis, gastroenteritis;

Benign, malignant and unspecified neoplasms (including cysts and polyps): neoplasm (unspecified);

Blood and lymphatic system disorders: thrombocytopenia, lymphadenopathy, bruising;

Endocrine disorders: hyperthyroidism§, virilization;

Metabolism and nutrition disorders: hypertriglyceridemia§, hyperuricemia, hypothyroidism§, increased appetite§;

Psychiatric disorders: excitement, somnolence, aggressive behavior, nervousness, apathy, behavioral disorders, decreased concentration, sleep disorders, dream abnormalities, anxiety, sleepwalking, suicidal ideation;

Nervous system disorders: tremor, confusion, hyperkinesia, dysphonia, paresthesia, hyperesthesia, hypoesthesia, concentration difficulties, somnolence;

Eye disorders: conjunctivitis, eye pain, visual disturbances, lacrimal gland dysfunction;

Vascular disorders: Raynaud's phenomenon, flushing, pallor;

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal congestion, nasal mucosal irritation, pulmonary infection, rhinitis, sneezing, tachypnea;

Gastrointestinal disorders: constipation, dyspepsia, gastroesophageal reflux, gastrointestinal disorders, glossitis, diarrhea, oral ulcers, rectal disorders, stomatitis including ulcerative and ulcerative-gangrenous, toothache, dental disorders, right upper quadrant abdominal pain;

Hepatobiliary disorders: liver function abnormalities;

Skin and subcutaneous tissue disorders: pruritus, acne, eczema, skin lesions, nail disorders, dry skin, photosensitivity reactions, maculopapular rash, pigmentation disorders, acneiform eruptions, skin disorders, nail disorders, skin color changes, erythema, increased sweating, hematoma;

Renal and urinary disorders: enuresis, micturition disorder, urinary incontinence;

Reproductive system and breast disorders: females: amenorrhea, menorrhagia, menstrual cycle disorder, vaginal disorders/pathology; males: testicular pain;

General disorders and administration site conditions: chest pain, injection site pain, asthenia, erythema, swelling;

Injury, poisoning and procedural complications: skin laceration.

Clinical studies conducted throughout the use of Bioferon demonstrated an acceptable safety profile consistent with other interferon alfa-2b products in both adult and pediatric patients.

If Bioferon is to be prescribed in combination with ribavirin for patients with chronic hepatitis C, consider the safety information for ribavirin regarding adverse reactions associated with its use.

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after marketing authorization. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with local requirements.

Shelf Life. 2 years.

Storage Conditions

Store out of reach of children, at 2 to 8 °C. Do not freeze.

Incompatibilities

This medicinal product must not be mixed with any other medicinal products.

Special attention is required when co-administering with medicinal products described in the section "Interaction with Other Medicinal Products and Other Forms of Interaction".

BIOFERON for injection should be reconstituted only with sterile water for injection.

Packaging. 1 vial per carton.

Prescription Category. Prescription only.

Manufacturer. Biosidus S.A.

Manufacturer's Address and Place of Business.

Constitucion 4234 (zip code C1254ABX), of the City of Buenos Aires, Argentine Republic.