Alfarekin® interferon alpha-2b recombinant human

INSTRUCTION for medical use of the medicinal product Alfarekin® Recombinant human interferon alpha-2b

Composition:

Active substance: recombinant human interferon alpha-2b,

1 vial contains 3 million IU of recombinant human interferon alpha-2b;

Excipients: sodium chloride, dextran 70, potassium dihydrogen phosphate, anhydrous sodium hydrogen phosphate.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: lyophilized powder or porous mass, white in color.

Pharmacotherapeutic group.
Immunostimulants. Interferon alpha-2b. ATC code L03AB05.

Pharmacological Properties

Pharmacodynamics

Alfarekin® is a pharmaceutical form of recombinant human alpha-2b interferon, synthesized by Escherichia coli cells based on a gene encoding a product identical to human alpha-2b interferon, using phage-dependent genetic engineering biotechnology. The specific activity of Alfarekin® is measured in international units. The drug is released in the form of a lyophilisate.

Alfarekin®, like natural leukocyte interferon, possesses three main types of biological activity: immunomodulatory, antiviral, and antitumor.

The mechanism of action of Alfarekin® is based on interferon binding to specific receptors on cells of the body, thereby inducing a complex of intracellular mechanisms leading to the production of enzymes that prevent viral replication, enhance macrophage phagocytic activity, increase lymphocyte-specific cytotoxicity against target cells, and inhibit proliferation of metastasizing cells.

Pharmacokinetics

Not studied.

Clinical characteristics.

Indications.

Alfarekin® is used in combination therapy for:

• acute and chronic viral hepatitis B (moderate and severe);
• chronic hepatitis C;
• skin and eye melanoma;
• multiple myeloma;
• chronic myeloid leukemia;
• hairy cell leukemia;
• non-Hodgkin’s malignant lymphomas, specifically follicular lymphoma.

Contraindications.

• Hypersensitivity to interferon alfa-2b or to any other components of the drug;
• severe cardiovascular diseases (including decompensated heart failure, recent myocardial infarction, severe arrhythmia);
• severe renal or hepatic dysfunction, including due to metastases;
• epilepsy and/or other central nervous system (CNS) disorders (including functional disorders);
• chronic hepatitis with decompensated cirrhosis of the liver;
• chronic hepatitis in patients undergoing or who have recently undergone immunosuppressive therapy, except for a short course of corticosteroid therapy;
• autoimmune hepatitis or history of autoimmune disease; contraindicated in transplant recipients following immunosuppressive therapy;
• pre-existing thyroid disorders not controlled by conventional treatment;
• presence of severe visceral involvement in patients with Kaposi’s sarcoma;
• psoriasis, sarcoidosis, if potential benefit does not outweigh potential risk;
• combination of Alfarekin® with telbivudine;
• pregnancy (safety of the drug during pregnancy has not been established).

Children and adolescents

Severe psychiatric conditions, particularly severe depression, suicidal ideation, or suicide attempts, current or in history.

Combination therapy with ribavirin

When using Alfarekin® and ribavirin in combination therapy for chronic hepatitis C, also consider the contraindications for ribavirin.

Interaction with other medicinal products and other forms of interaction.

Since interferon alfa alters cellular metabolism, there is a potential for modifying the effects of other medicinal products. Oxidative metabolic processes may be altered, which should be considered when co-administering drugs metabolized via this pathway (cimetidine, phenytoin, warfarin, theophylline, aminophylline, diazepam, propranolol). Serum theophylline concentrations should be monitored and dosage regimen adjusted if necessary.

The drug should be used with caution when administered concomitantly with opioid medicinal products, analgesics, hypnotics, and sedatives (potentially causing myelosuppressive effects).

Pulmonary disorders, infiltrates, pneumonia (in some cases fatal) have been rarely observed in patients receiving interferon alfa therapy. The etiology has not been established. These symptoms have been more frequently reported when "shosai-koto" (a Chinese herbal medicine) was used concomitantly with interferon alfa.

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

Synergism of adverse effects (regarding leukocyte count) has been described with concomitant use of interferon alfa and zidovudine. In patients who received both drugs simultaneously, the incidence of neutropenia was higher than in those treated with zidovudine alone.

If Alfarekin® is administered in combination with ribavirin to patients with chronic hepatitis C, see also the prescribing information for ribavirin.

A clinical study of the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 mcg once weekly by subcutaneous injection, showed that this combination is associated with an increased risk of peripheral neuropathy. The mechanism of this reaction is unknown. In addition, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been demonstrated. Therefore, the combination of Alfarekin® with telbivudine is contraindicated.

Special precautions for use.

Alfarekin® should be administered under the supervision of a physician. Patients should be informed about the benefits of this therapy and possible adverse reactions.

If an adverse reaction does not diminish or intensifies, the dose of the drug should be reduced by 50% or treatment should be discontinued. Depending on individual sensitivity and the prescribed dose, patients may experience a slowing of psychomotor reactions, manifested as somnolence, weakness, and increased fatigue.

Fever

Since fever may occur as part of an influenza-like syndrome, which is a common phenomenon during interferon therapy, other causes of persistent fever should be ruled out. It is recommended to administer the medicinal product concomitantly with antihistamine and antipyretic therapy.

Need for adequate hydration

Adequate hydration must be ensured during treatment, as hypotension associated with dehydration may occur in some patients.

Hypersensitivity reactions

In the event of an immediate-type hypersensitivity reaction (urticaria, angioedema, bronchospasm, anaphylaxis), the drug should be discontinued immediately and appropriate measures taken. Transient skin rash does not require discontinuation of therapy.

Psychiatric disorders and central nervous system (CNS) disorders

In some patients receiving interferon alfa-2b preparations, severe adverse reactions of the CNS, particularly depression, suicidal ideation, and suicide attempts, have been observed during treatment and even after its discontinuation, mainly within the subsequent 6 months. In children and adolescents treated with interferon alfa-2b in combination with ribavirin, suicidal thoughts and suicide attempts occurred significantly more frequently (2.4% vs. 1%) compared to adults, both during treatment and within 6 months after therapy completion. As in adults, children and adolescents also experienced other psychiatric adverse effects (e.g., depression, emotional instability, and somnolence). Other CNS-related adverse reactions, including aggressive behavior (sometimes directed toward others, e.g., homicidal ideation), bipolar disorders, mania, confusion, and changes in mental status, have been observed during treatment with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms occur, the physician must consider the potential seriousness of these adverse effects and decide on the need for appropriate treatment. If psychiatric symptoms persist or worsen, suicidal ideation occurs, or aggressive behavior toward others is observed, discontinuation of Alfarekin® treatment and provision of appropriate psychiatric assistance are recommended.

Patients with severe psychiatric disorders, including in medical history

If interferon alfa-2b treatment is deemed necessary for adults with severe psychiatric disorders, including in their history, therapy should only be initiated after appropriate individual psychiatric evaluation and treatment of the psychiatric condition.

The use of interferon alfa-2b in children and adolescents with severe psychiatric disorders, including in their history, is contraindicated.

Patients using narcotic substances / substance abuse

Patients infected with hepatitis C virus (HCV) who use narcotic substances (alcohol, cannabis, etc.) have an increased risk of developing psychiatric disorders or exacerbation of existing psychiatric disorders during interferon alfa therapy. If interferon alfa treatment is necessary for these patients, the presence of concomitant psychiatric disorders and potential substance use should be assessed before initiating therapy. A psychiatrist or addiction specialist should be involved, if necessary, to evaluate the patient's condition and monitor them closely during and even after therapy completion, and to promptly initiate corrective measures. Alcohol consumption must be excluded during treatment with the drug.

HIV/HCV co-infection

In patients co-infected with HIV undergoing highly active antiretroviral therapy (HAART), the risk of lactic acidosis increases. Caution is advised when adding Alfarekin® and ribavirin treatment to HAART. The risk of anemia increases in patients receiving Alfarekin® and ribavirin in combination with zidovudine.

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

HBV/HCV co-infection

Cases of reactivation of hepatitis B (some with severe outcomes) have been reported in patients co-infected with hepatitis B and C viruses treated with interferon preparations. The frequency of such reactivation was low. All patients should be tested for hepatitis B before initiating interferon therapy for hepatitis C. Patients co-infected with hepatitis B and C should be monitored and treated according to current clinical guidelines.

Thyroid gland disorders

Thyroid disorders, including hypothyroidism or hyperthyroidism (in 2.8% of patients during clinical trials), have been observed infrequently in adult patients receiving interferon alfa-2b therapy for viral hepatitis C. Thyroid function disorders were managed with appropriate conventional therapy. The mechanism by which Alfarekin® may affect thyroid status is unknown. Before prescribing the drug for prolonged use at doses of 3 million IU or higher, thyroid function testing is recommended. Treatment may be initiated provided that thyrotropin (TSH) levels are within normal limits. If TSH level changes are detected, appropriate therapy should be administered. Alfarekin® treatment may be initiated if TSH levels can be maintained within the normal range. Monitoring of TSH levels during treatment is also advisable. If symptoms of thyroid dysfunction occur during Alfarekin® therapy, TSH levels should be determined. Treatment with this drug may be continued if TSH levels can be maintained within the normal range. After discontinuation of therapy, thyroid function impaired due to drug administration does not recover.

Additional monitoring of thyroid function in children and adolescents

In children and adolescents undergoing prolonged treatment with interferon preparations, thyroid function should be monitored every 3 months (including TSH level determination).

Laboratory tests

All patients should undergo a complete peripheral blood count with mandatory qualitative and quantitative blood parameter assessment, as well as a biochemical blood test, including electrolytes, calcium, liver enzymes, bilirubin, and creatinine, before starting and regularly during treatment. Serum albumin levels and prothrombin time must be carefully monitored in all patients receiving the drug.

During therapy in patients with chronic hepatitis B or C, the following schedule for monitoring laboratory parameters is recommended: weeks 1, 2, 4, 8, 12, 16, and then once every two months throughout the treatment course. If ALT levels rise to values twice or more above baseline levels, Alfarekin® treatment may be continued provided there are no signs of hepatic failure. In this case, ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin should be measured every 2 weeks.

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

In patients with myeloma, periodic monitoring of kidney function is required.

Hypertriglyceridemia

Hypertriglyceridemia and exacerbation of hypertriglyceridemia, sometimes severe, have been observed during treatment with alpha interferon preparations; therefore, monitoring of lipid levels is recommended.

Adverse effects, including prolongation of coagulation markers and liver function disorders

Severe and moderate adverse effects may require dose adjustment or, in some cases, discontinuation of Alfarekin® treatment. Alpha interferon preparations increase the risk of hepatic decompensation and death in patients with liver cirrhosis. Discontinuation of treatment is recommended for patients with chronic hepatitis who develop prolonged coagulation markers, which may indicate hepatic failure. Close monitoring is required for any patient who develops liver function abnormalities during Alfarekin® treatment, and therapy should be discontinued if symptoms progress. Liver enzyme levels and liver function should be carefully monitored in patients with cirrhosis.

Combination therapy with ribavirin

When using combination therapy with ribavirin, the warnings regarding ribavirin use must be considered.

Ribavirin causes serious congenital malformations when used during pregnancy. Patients taking Alfarekin® in combination with ribavirin should avoid pregnancy. Women of childbearing potential must use effective contraception during treatment and for 4 months after treatment completion. Male patients and their partners must use effective contraception during treatment and for 7 months after treatment completion.

Concomitant chemotherapy

The use of interferon alfa in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) increases the risk of toxicity, which may be life-threatening. 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 Alfarekin® is required when used concomitantly with chemotherapeutic agents. When Alfarekin® is used together with hydroxyurea, an increased frequency and severity of cutaneous vasculitis may occur.

Autoantibodies and autoimmune disorders

The development of autoantibodies and autoimmune disorders has been observed during treatment with alpha interferons. Patients predisposed to autoimmune disorders belong to a high-risk group. Patients with signs of autoimmune disorders require continuous monitoring, and the benefit/risk ratio of continuing interferon therapy should be re-evaluated. Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been observed in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be discontinued and corticosteroid therapy considered.

Patients with debilitating diseases

Alfarekin® should be used cautiously in patients with chronic debilitating conditions, such as a history of pulmonary diseases (e.g., chronic obstructive pulmonary disease), and in patients with diabetes prone to ketoacidosis. Close monitoring is also required for patients with coagulation disorders (e.g., thrombophlebitis, pulmonary artery embolism) or severe myelosuppression.

Patients with cardiac disorders

There is no evidence of direct cardiotoxicity of interferon; however, hyperthermia and chills, which commonly accompany treatment, may potentially exacerbate existing cardiac conditions. Interferon alfa-2b treatment should be administered under strict physician supervision in patients with a history of chronic heart failure, myocardial infarction, and/or arrhythmias, including in their history. Patients with a history of cardiac disorders and/or advanced cancer are recommended to undergo ECG before and during the treatment course. Cardiac rhythm disturbances (mainly supraventricular) usually respond to conventional therapy but may require discontinuation of the drug. Data on the use of combination therapy in children and adolescents with a history of cardiac disorders are lacking.

Hypotension

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

Respiratory disorders

Rarely, patients receiving alpha interferon developed lung infiltrates, pneumonitis, and pneumonia, including fatal cases. The etiology of these events is not established. These symptoms were more frequently observed when "shosaikoto" (a Chinese herbal medicinal product) was used concomitantly with alpha interferon. All patients developing fever, cough, dyspnea, and other respiratory symptoms should undergo chest X-ray. Continuous monitoring is required in the presence of infiltrates on X-ray or signs of impaired lung function, and alpha interferon should be discontinued if necessary. Although these symptoms were more frequently observed in patients with chronic hepatitis C receiving alpha interferon, they have also been reported in cancer patients undergoing alpha interferon therapy. Immediate discontinuation of alpha interferon and corticosteroid treatment facilitate resolution of pulmonary adverse effects.

Stupor, coma, and encephalopathy

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

Ocular adverse effects

Ocular adverse effects, including retinal hemorrhages, cotton-wool spots on the retina, serous retinal detachment, and obstruction of the retinal artery or vein, have been observed in some cases after treatment with alpha interferons. All patients should undergo ophthalmological examination before starting therapy. All patients complaining of decreased visual acuity, visual field defects, or other ophthalmological symptoms during Alfarekin® treatment should undergo immediate complete ophthalmological examination. Periodic ophthalmological examinations during Alfarekin® therapy are especially recommended for patients with conditions potentially associated with retinopathy, such as diabetes mellitus or arterial hypertension. Treatment with the drug should be discontinued in case of new-onset or worsening of existing ophthalmological disorders.

Dental and periodontal disorders

Dental and periodontal disorders, potentially leading to tooth loss, have been reported in patients receiving combination therapy with alpha interferon and ribavirin. Dry mouth during prolonged combination therapy with alpha interferon and ribavirin may lead to damage of teeth and oral mucosa. Patients should be advised to brush their teeth thoroughly twice daily and undergo regular dental check-ups. Patients should be advised to rinse their mouth thoroughly after vomiting.

Patients with psoriasis and sarcoidosis

Given data indicating that alpha interferon may exacerbate existing psoriasis and sarcoidosis, Alfarekin® should be used in patients with these conditions only if the potential benefit outweighs the potential risk.

Rejection of kidney and liver transplants

Preliminary data suggest that interferon alfa therapy may be associated with an increased frequency of kidney transplant rejection. Cases of liver transplant rejection have also been reported during interferon therapy. In patients after organ or bone marrow transplantation, pharmacological immunosuppression may be less effective, as interferons exert an immunostimulatory effect on the immune system.

Effect on fertility

Interferon may reduce fertility. Decreased serum concentrations of estradiol and progesterone have been reported in women receiving human leukocyte interferon. Therefore, effective contraception must be used in women of reproductive age when using the drug.

Treatment with the drug should be discontinued in case of: prolonged blood clotting time (in patients with chronic hepatitis), pulmonary syndrome symptoms and radiological detection of infiltrates, onset or worsening of visual disturbances, thyroid dysfunction (TSH levels outside normal range), decreased serum albumin levels, and reduced prothrombin time.

The product does not contain preservatives; therefore, to avoid bacterial contamination, the solution for parenteral administration should be used immediately.

Alfarekin® contains sodium compounds — less than 1 mmol sodium (23 mg) per 1 ml, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Use of the drug during pregnancy and breastfeeding is contraindicated (safety of use during pregnancy has not been established).

Ability to affect reaction speed when driving or operating machinery.

Depending on dose, treatment regimen, and individual sensitivity to alpha interferon, treatment may be accompanied by somnolence, weakness, fatigue, and lead to reduced psychomotor reaction speed. In such cases, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

Alfarekin® solution is administered intramuscularly, subcutaneously, intravenously, or parabulbarly.

Acute Viral Hepatitis B:

• Administer intramuscularly, 1 million IU (in severe cases – 2 million IU) twice daily for 10 days. This regimen may be extended up to 2–3 weeks depending on the patient's clinical status, or continued at a dose of 1 million IU twice weekly for several weeks.

Chronic Viral Hepatitis B:

• Administer intramuscularly, 3–4 million IU three times weekly for 2 months.

Chronic Viral Hepatitis C:

• Administer intramuscularly, 3 million IU three times weekly for 6 months when used as monotherapy or in combination with nucleoside analogs. HCV RNA levels should be assessed after 3–4 months; continue treatment only if HCV RNA is undetectable. Duration of therapy: 12 to 18 months with monotherapy; 6 months in combination with ribavirin. For genotype 1 and high baseline viral RNA load, if HCV RNA is undetectable 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 sex, and progressive fibrosis.

Cutaneous Melanoma:

• As adjuvant to surgical treatment and for induction of remission: intravenous infusion of 20 million IU/m² (infusion over 20 minutes) five times weekly for 4 weeks; maintenance therapy: subcutaneous administration of 10 million IU/m² three times weekly (every other day) for 48 weeks.

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

Uveal Melanoma:

• Administer parabulbarly once daily at 1 million IU for 10 days; repeat 10-day courses after 20 days, twice. The total treatment course with Alfarekin® lasts 48 weeks. Repeat courses after 45 days may be necessary. Alfarekin® treatment is combined with photodestruction of the tumor and beta-applications.

Multiple Myeloma:

• Administer intramuscularly daily for 10 days at 3 million IU per injection; repeated courses: once every 1.5–3 months (4–6 times per year).

Chronic Myeloid Leukemia:

• Administer subcutaneously at 3 million IU/m² daily or every other day, gradually increasing the dose to 5 million IU/m² daily or every other day under physician supervision until complete hematological remission is achieved (leukocyte count in peripheral blood not exceeding 10 × 10⁹/L) or for up to 18 months.

Hairy Cell Leukemia:

• Administer intramuscularly, 3 million IU three times weekly (every other day) for 4–6 weeks. Upon achieving remission, maintenance therapy is administered: 3 million IU every other day up to 12 months.

Non-Hodgkin’s Malignant Lymphomas, specifically Follicular Lymphoma:

• Administer intramuscularly, 3 million IU three times weekly for 12–18 months as maintenance therapy following remission achieved with chemotherapy. In cases of partial remission, other chemotherapy protocols are indicated, followed by Alfarekin® therapy: 3 million IU intramuscularly three times weekly for 18 months.

Preparation of the Drug Solution.

The drug solution should be prepared immediately before use. Use water for injections as solvent (if the solution is intended for subcutaneous, intradermal, or intramuscular administration). To prepare the solution, dissolve the contents of the vial in 1 mL of water for injections.

Preparation and Administration of Intravenous Infusion.

Begin infusion of 0.9% sodium chloride solution at a rate of 200 mL/hour 30 minutes before starting Alfarekin® infusion, and complete it immediately before drug administration. To prepare the infusion solution, first dissolve Alfarekin® in water for injections (1 mL of water per dose of the drug), then withdraw the required amount and add it to 50 mL of 0.9% sodium chloride solution. Administer the prepared solution intravenously by drip infusion over 30 minutes. After completion of Alfarekin® infusion, continue infusion of 0.9% sodium chloride solution at a rate of 200 mL/hour for 10 minutes.

The injectable solution of the drug should be used immediately. For intranasal use, the solution may be stored for up to 1 day at a temperature of 2 to 8 °C.

Children.

Use in pediatric practice in combination with ribavirin for treatment of children aged 3 years and older and adolescents with previously untreated chronic hepatitis C, without hepatic decompensation, and who are HCV RNA positive. When deciding not to delay treatment until adulthood, it is important to consider that combination therapy has been associated with growth retardation leading to reduced final adult height in some patients. The decision to treat should be made on a case-by-case basis.

Overdose.

Cases of overdose with Alfarekin® have not been reported to date. However, as with overdose of any medicinal product, symptomatic therapy is recommended, along with monitoring of vital organ functions and careful observation of the patient's condition.

Adverse reactions.

When Alfarekin® is used for the treatment of patients with chronic hepatitis C in combination with ribavirin, refer to the ribavirin product information for adverse effects associated with ribavirin use.

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

Subcutaneous administration of Alfarekin®, as with all other alpha interferon products, is usually accompanied by a flu-like syndrome characterized by elevated body temperature, chills, headache, muscle pain, joint pain, and lethargy. These adverse effects, which are mild to moderate in severity, are dose-dependent and typically occur only during the first days of treatment, then gradually diminish and resolve. These symptoms may be prevented or significantly reduced by administering paracetamol at a dose of 0.5–1 g 30–40 minutes prior to injection. Vomiting, dizziness, and hot flashes are less commonly observed.

Infections and infestations, including pharyngitis*, viral infection*, bronchitis, sinusitis, herpes simplex, rhinitis, fungal infection, bacterial infection, pulmonary infection, otitis media, dental abscess, herpes simplex, urinary tract infections, vaginitis, gastroenteritis, pneumonia**, sepsis, reactivation of hepatitis B in patients co-infected with HBV/HCV.

Benign, malignant and unspecified neoplasms (including cysts and polyps), including neoplasms (unspecified).

Blood and lymphatic system disorders, including anemia, neutropenia, leukopenia, thrombocytopenia, which are reversible upon dose reduction; lymphadenopathy, lymphopenia, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura.

Immune system disorders**, including sarcoidosis, sarcoidosis exacerbation, systemic lupus erythematosus, hemorrhagic and thrombotic thrombocytopenic purpura, vasculitis, rheumatoid arthritis (new onset or exacerbation)**, Vogt-Koyanagi-Harada syndrome, acute hypersensitivity reactions (including urticaria, angioedema, bronchospasm, anaphylactic reaction**).

Endocrine disorders, including hypothyroidism**, hyperthyroidism**, virilization, diabetes, worsening of diabetes mellitus.

Metabolism and nutrition disorders, including anorexia, hypocalcemia, dehydration, hyperuricemia, thirst, hyperglycemia, hypertriglyceridemia***, increased appetite, electrolyte imbalance.

Psychiatric disorders**, including depression, insomnia, fear, emotional lability*, behavioral disorders, agitation, somnambulism, anxiety, nervousness, sleep disturbances, dream abnormalities, apathy, confusion, sleep disorders, decreased libido, suicidal ideation, suicide, suicide attempts, aggressive behavior (sometimes directed toward others), psychosis including hallucinations, homicidal ideation, mental status changes***, mania, bipolar disorder.

Nervous system disorders**, including dizziness, headache, difficulty concentrating, dry mouth, hyperkinesia, tremor, dysphonia, ataxia, paresthesia, hypoesthesia, hyperesthesia, migraine, hot flashes, difficulty concentrating, somnolence, taste disturbances, peripheral neuropathy, cerebral hemorrhage, cerebrovascular ischemia, seizures, consciousness disturbance syndrome, encephalopathy, mononeuropathy, coma***.

Eye disorders, including decreased visual acuity, conjunctivitis, visual disturbances, lacrimal gland disorders, eye pain, retinal hemorrhage**, retinopathy (including macular edema), obstruction of retinal vein or artery**, optic neuritis, optic disc edema, loss of visual acuity or visual fields, "cotton wool" spots on retina***, serous retinal detachment.

Ear and labyrinth disorders, including dizziness, tinnitus, hearing impairment or hearing loss.

Cardiac disorders, including palpitations, tachycardia, pericarditis, cardiomyopathy, myocardial infarction, myocardial ischemia, congestive heart failure, pericardial effusion, arrhythmia.

Vascular disorders, including hypertension, peripheral ischemia, hypotension***, hyperemia, pallor.

Respiratory, thoracic and mediastinal disorders, including dyspnea*, tachypnea, epistaxis, cough*, nasal bleeding, respiratory disturbances, nasal congestion, nasal mucosal irritation, rhinorrhea, sneezing, dry non-productive cough, pulmonary infiltrates**, pneumonia**, pulmonary fibrosis, pulmonary arterial hypertension****.

Gastrointestinal disorders, including nausea/vomiting, abdominal pain, stomatitis, dyspepsia, ulcerative and ulceronecrotic stomatitis, right upper quadrant abdominal pain, dyspepsia, glossitis, gastroesophageal reflux, gingivitis, constipation, diarrhea, pancreatitis, ischemic colitis, ulcerative colitis, gingival bleeding, unspecified periodontal disorders, toothache, unspecified dental disorders, tongue pigmentation***.

Hepatobiliary disorders, including liver function abnormalities, hepatomegaly, hepatotoxicity (including fatal cases).

Skin and subcutaneous tissue disorders, including alopecia, rash*, photosensitivity reaction, maculopapular rash, erythematous rash, eczema, acne, skin lesions, nail disorders, pigmentation disorders, pruritus*, dry skin, erythema, skin disorders, hematoma, increased sweating, psoriasis (new onset or exacerbation)***, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Musculoskeletal and connective tissue disorders, including myalgia, arthralgia, musculoskeletal pain, arthritis, rhabdomyolysis, myositis, leg cramps, back pain.

Renal and urinary disorders, including urinary frequency, enuresis, urinary retention, urinary incontinence, renal failure, nephrotic syndrome.

Reproductive system and breast disorders, including in women: amenorrhea, breast pain, dysmenorrhea, menorrhagia, menstrual cycle disturbances, vaginal disorders; in men: testicular pain.

General disorders and administration site conditions, including injection site inflammation, allergic reaction at injection site*, fatigue, chills, fever**, flu-like symptoms**, asthenia, irritability, chest pain, malaise, injection site pain, necrosis at injection site, facial swelling.

Laboratory abnormalities, including weight loss, growth retardation (decreased growth velocity and/or body weight appropriate for age).

Injury and poisoning, including skin laceration.

* These adverse effects are common only during monotherapy with alpha interferon.

** See section "Special precautions".

*** Class warning for interferon products; see below for pulmonary arterial hypertension.

Adverse reactions observed in patients with hepatitis C are typical for alpha interferon-2b use in other indications, with increased frequency at higher doses. For example, during high-dose alpha interferon-2b therapy as adjuvant treatment in melanoma patients, adverse reactions such as fatigue, fever, myalgia, neutropenia, anemia, anorexia, nausea and vomiting, diarrhea, chills, flu-like symptoms, depression, alopecia, taste disturbances, and dizziness occurred more frequently than in hepatitis C clinical trials. Severity of adverse effects also increases with high-dose therapy (66% and 14% of patients experienced WHO grade 3 and 4 toxicities, respectively), compared to mild or moderate severity typically associated with lower doses. Adverse effects are usually manageable through dose adjustments.

Cardiovascular adverse effects, particularly arrhythmias, are primarily associated with pre-existing cardiovascular disease and occur after therapy with cardiotoxic agents. Cardiomyopathy, which is reversible upon discontinuation of alpha interferon therapy, is rarely observed in patients without prior cardiac symptoms.

Cases of pulmonary arterial hypertension (PAH) associated with alpha interferon products have been reported, particularly in patients with PAH risk factors (e.g., portal hypertension, HIV infection, liver cirrhosis). These events occurred at various times, usually several months after initiation of alpha interferon therapy.

A wide range of autoimmune and immune-mediated disorders may occur during alpha interferon therapy, including thyroid dysfunction, systemic lupus erythematosus, rheumatoid arthritis (new onset or exacerbation), hemorrhagic and thrombotic thrombocytopenic purpura, vasculitis, and neuropathy, including mononeuropathy.

Clinically significant laboratory abnormalities, more frequently observed at doses exceeding 10 million IU per day, include decreased granulocyte and leukocyte counts; reduced hemoglobin and platelet counts; increased alkaline phosphatase, LDH, serum creatinine, and blood urea nitrogen levels. Moderate, usually reversible pancytopenia has also been observed. Elevated ALT/AST levels as deviations from normal have been observed in some non-hepatitis C patients, and in some patients with chronic hepatitis B, coinciding with clearance of viral DNA polymerase.

The adverse reaction profile in children and adolescents is generally similar to that in adults, although growth suppression is a specific pediatric concern. Moreover, suicidal ideation or suicide attempts occur more frequently in children and adolescents compared to adult patients. As in adults, other psychiatric disorders (e.g., depression, emotional lability, somnolence) have also been observed in children and adolescents. In addition, injection site reactions, fever, anorexia, vomiting, and emotional lability are more common in children and adolescents than in adult patients.

Shelf life. 3 years from the date of manufacture in bulk form.

Storage conditions.

Store in original packaging at 2 to 8 °C in a place inaccessible to children.

Packaging.

Lyophilisate for solution for injection, 3 million IU per vial.

10 vials of lyophilisate per cardboard box;

5 vials of lyophilisate with 5 ampoules of solvent (2 mL water for injection) per cardboard box;

1 vial of lyophilisate with 1 ampoule of solvent (2 mL water for injection) per cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "VALARTIN PHARMA" (bulk production by the manufacturer LLC "Scientific-Production Company "Interpharmbiotek", Ukraine)

Manufacturer's location and address of business activity.

60, Hrushevskoho St., Chayky, Kyiv-Sviatoshynskyi District, Kyiv Oblast, 08135, Ukraine