Alpharekin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALPHAREKIN® (ALPHAREKIN®)

Composition:

Active substance: recombinant human interferon alpha-2b; 1 vial contains 1 million IU or 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, hygroscopic.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics.

Alfarekin® is a medicinal form of recombinant human alpha-2b interferon. Recombinant alpha-2b interferon is a highly purified, water-soluble protein with a molecular weight of 19,300 daltons, 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 produced in a lyophilized form.

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 that lead to the production of enzymes preventing viral replication, enhancing macrophage phagocytic activity, specific lymphocyte cytotoxicity against target cells, and inhibition of proliferating metastatic cells.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

Alfarekin® is used in complex therapy for:

• acute and chronic viral hepatitis B (moderate and severe forms);
• chronic hepatitis C;
• acute viral, bacterial, and mixed infections (including acute respiratory viral infection in children, including newborns, acute diarrheal syndrome in newborns);
• acute and chronic septic diseases of viral and bacterial origin, including disseminated forms of acute and chronic sepsis;
• herpes infections of various localizations: herpes zoster, multiple cutaneous herpes eruptions; genital herpes infection; herpetic keratoconjunctivitis and keratouveitis; acute herpetic stomatitis in children;
• chronic urogenital chlamydia;
• nervous system lesions with mono- and polyradicular pain syndromes;
• multiple sclerosis;
• laryngeal papillomatosis;
• skin and eye melanoma; Kaposi's sarcoma; myeloma; chronic myeloid leukemia; hairy cell leukemia; non-Hodgkin's malignant lymphomas, specifically follicular lymphoma.

Contraindications.

• Hypersensitivity to interferon alpha-2b or to any other component of the medicinal product;
• 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);
• chronic hepatitis with decompensated liver cirrhosis;
• chronic hepatitis in patients who are undergoing or have recently completed immunosuppressive therapy, except for a short course of corticosteroid therapy;
• autoimmune hepatitis or history of autoimmune disease; contraindicated in transplant recipients following immunosuppressive therapy;
• 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 condition, especially severe depression, suicidal thoughts or suicide attempts, current or in history.

Combination therapy with ribavirin

When Alfarekin® and ribavirin are used in combination therapy for chronic hepatitis C, contraindications for ribavirin must also be considered.

Interaction with other medicinal products and other forms of interaction.

Since interferon alpha alters cellular metabolism, there is a potential for modification of the effects of other medicinal products. It may alter oxidative metabolic processes—this should be considered when co-administering drugs metabolized via this pathway (cimetidine, phenytoin, warfarin, theophylline, aminophylline, diazepam, propranolol). Serum theophylline concentration should be monitored and dosage regimen adjusted as necessary.

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

Pulmonary disorders, infiltrates, pneumonia (in some cases fatal) have been rarely observed in patients receiving interferon alpha therapy. The etiology has not been established. These symptoms have been more frequently reported in patients concurrently receiving "shosaikoto" (a Chinese herbal medicine) with interferon alpha.

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 when interferon alpha and zidovudine are used concomitantly. 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 medical instructions for ribavirin.

A clinical study of the combination of telbivudine, 600 mg daily, with pegylated interferon alpha-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. Furthermore, 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 used under the supervision of a physician. Patients should be informed about the benefits of this therapy and possible adverse reactions.

If an adverse effect does not diminish or intensifies, the dose of the medicinal product should be reduced by 50% or treatment should be discontinued. Depending on individual sensitivity and the prescribed dose, patients may experience slowed psychomotor reactions: drowsiness, weakness, increased fatigue.

Fever

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

Need for adequate hydration

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

Hypersensitivity reactions

In case of an immediate-type hypersensitivity reaction (e.g., 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 during treatment with interferon alfa-2b, and even after discontinuation of therapy—mainly within the following 6 months—severe adverse effects on the CNS, particularly depression, suicidal thoughts, and suicide attempts, have been observed. In children and adolescents undergoing treatment with interferon alfa-2b in combination with ribavirin, suicidal thoughts and suicide attempts occurred more frequently than in adults (2.4% vs. 1%) during treatment and within 6 months after therapy completion. As in adults, children and adolescents experienced other psychiatric side effects (e.g., depression, emotional lability, drowsiness). Other CNS effects, 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 interferon alfa. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms occur, the physician should consider the potential seriousness of these adverse effects and decide on the need for appropriate treatment. If psychiatric symptoms persist or worsen, or if suicidal ideation or aggressive behavior toward others occurs, discontinuation of Alfarekin® therapy is recommended, and appropriate psychiatric care should be provided.

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 who use/abuse psychoactive substances

Patients infected with hepatitis C virus (HCV) who use psychoactive substances (alcohol, cannabis, etc.) have an increased risk of developing psychiatric disorders or exacerbation of existing psychiatric conditions during interferon alfa therapy. If interferon alfa therapy is necessary for these patients, the presence of comorbid psychiatric disorders should be assessed before treatment initiation, and the potential for substance use should be evaluated. If necessary, a psychiatrist or addiction specialist should be involved to assess and closely monitor the patient during and even after therapy, and to timely initiate appropriate corrective measures. Alcohol consumption must be avoided during treatment with this drug.

HIV and hepatitis C virus co-infection

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

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

Hepatitis B and C virus co-infection

Cases of reactivation of hepatitis B (some with severe consequences) have been reported in patients co-infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) who were 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. Co-infected patients should be monitored and treated according to current clinical guidelines.

Thyroid gland disorders

Thyroid dysfunction, including hypothyroidism or hyperthyroidism (in 2.8% of patients in clinical trials), has been observed infrequently in adult patients receiving interferon alfa-2b therapy for chronic hepatitis C. Thyroid dysfunction was managed with conventional therapy. The mechanism by which Alfarekin® may affect thyroid status is unknown. Before initiating long-term treatment at doses of 3 million IU or higher, thyroid function testing is recommended. The drug may be initiated if thyroid-stimulating hormone (TSH) levels are within normal limits. If TSH level changes are detected, appropriate therapy should be administered. Alfarekin® therapy 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 treatment with Alfarekin®, 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 dysfunction caused by the drug does not resolve.

Additional monitoring of thyroid function in children and adolescents

In children and adolescents undergoing long-term interferon therapy, thyroid function should be monitored every 3 months (e.g., by measuring TSH levels).

Laboratory tests

All patients should undergo a complete peripheral blood count before treatment initiation and regularly during therapy, including qualitative and quantitative blood parameter assessment, as well as biochemical blood testing, including electrolytes, calcium, liver enzymes, bilirubin, and creatinine. All patients receiving the drug should be closely monitored for serum albumin levels and prothrombin time.

During therapy for patients with chronic hepatitis B or C, the following laboratory monitoring schedule is recommended: weeks 1, 2, 4, 8, 12, 16, and then every 2 months throughout the treatment course. If alanine aminotransferase (ALT) levels increase to twice or more than baseline levels, treatment with Alfarekin® may be continued provided there is no hepatic insufficiency. In such cases, ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin levels should be monitored every 2 weeks.

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

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

Hypertriglyceridemia

Hypertriglyceridemia and exacerbation of hypertriglyceridemia, sometimes severe, have been observed during interferon alfa therapy; therefore, lipid level monitoring is recommended.

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

Moderate to severe adverse effects may require dose adjustment or, in some cases, discontinuation of Alfarekin® therapy. Interferon alfa 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 insufficiency. Patients who develop liver function abnormalities during Alfarekin® therapy should be closely monitored, and therapy should be discontinued if symptoms progress. Liver enzyme levels and liver function should be carefully monitored in cirrhotic patients.

Combination therapy with ribavirin

When using combination therapy with ribavirin, the warnings related to 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 reproductive age must use effective contraception during treatment and for 4 months after treatment completion. Male patients and their female 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 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 interferon alfa therapy. Patients predisposed to autoimmune disorders are at increased risk. Patients with signs of autoimmune disorders require ongoing monitoring, and the benefit-risk ratio of continuing interferon therapy should be reassessed. Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been observed in patients with chronic hepatitis C treated with interferon. VKH syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be discontinued, and corticosteroid therapy should be considered.

Patients with debilitating conditions

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 in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary artery thromboembolism) or severe myelosuppression.

Patients with cardiovascular disorders

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

Hypotension

Hypotension may occur during the course of treatment and within two days after therapy and may require additional treatment.

Respiratory system disorders

Rarely, patients receiving interferon alfa developed pulmonary infiltrates, pneumonitis, and pneumonia, including fatal cases. The etiology of these events is unclear. These symptoms have also been observed when "shosaikoto" (a traditional Chinese herbal medicine) was used concomitantly with interferon alfa. In patients presenting with fever, cough, dyspnea, or other respiratory symptoms, chest X-ray should be performed. Persistent monitoring is required if infiltrates or impaired lung function are detected, and discontinuation of interferon alfa may be necessary. Although these symptoms were more frequently observed in patients with chronic hepatitis C receiving interferon alfa, they have also been reported in cancer patients undergoing interferon alfa therapy. Immediate discontinuation of interferon alfa and corticosteroid treatment may help resolve 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 full 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, serous retinal detachment, and obstruction of the retinal artery or vein, have been observed in some cases after interferon alfa therapy. All patients should undergo ophthalmological examination before starting therapy. Any patient complaining of decreased visual acuity, visual field defects, or other ophthalmological symptoms during Alfarekin® treatment should undergo immediate and complete ophthalmological examination. Periodic ophthalmological examinations during Alfarekin® therapy are especially recommended for patients with conditions that may predispose to retinopathy, such as diabetes mellitus or arterial hypertension. Treatment should be discontinued if new or worsening ophthalmological disorders occur.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to tooth loss, have been reported in patients receiving combination therapy with interferon alfa and ribavirin. Dry mouth during prolonged combination therapy with interferon alfa and ribavirin may lead to dental and oral mucosal damage. 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 episodes of vomiting.

Patients with psoriasis or sarcoidosis

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

Kidney and liver transplant rejection

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 because interferons stimulate 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 should be used in women of reproductive age during treatment.

Treatment with the drug should be discontinued in the following cases: prolonged coagulation time (in patients with chronic hepatitis), pulmonary syndrome with radiologically detected infiltrates, onset or worsening of visual disturbances, thyroid dysfunction (TSH levels outside normal range), decreased serum albumin levels, and reduced prothrombin time.

The product contains no preservatives; therefore, to avoid bacterial contamination, the solution for parenteral administration should be used immediately, and any unused portion should be discarded.

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

Use during pregnancy or breastfeeding.

The use of the drug during pregnancy or breastfeeding is contraindicated (the safety of the drug 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 interferon alfa, therapy may be accompanied by drowsiness, weakness, fatigue, and reduced psychomotor reaction speed. In such cases, patients should refrain from driving or operating machinery.

Administration and Dosage.

Alfarekin® solution is administered intramuscularly, subcutaneously, intravenously, endolymphatically, rectally, parabulbarly, and intranasally.

Acute viral hepatitis B:

• Administer intramuscularly 1 million IU (in severe cases – 2 million IU) twice daily for 10 days. This course 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. The duration of monotherapy is 12–18 months; in combination with ribavirin – 6 months. 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.

Acute respiratory viral infection in children, including newborns:

• Administer intranasally 2–3 drops into each nostril 3–6 times daily for 3–5 days. The dosage for newborns is 20,000–50,000 IU/mL, and for other children – 100,000 IU/mL. It is permissible to insert cotton swabs moistened with Alfarekin® into the nasal passages (alternately) for 10–15 minutes.

Acute respiratory viral infection (including influenza) in adults:

• Administer intramuscularly 1–3 million IU, starting on days 1–2 of illness, for 3 days;
• Intranasally, administer 4–6 drops of Alfarekin® solution (100,000 IU/mL) into each nostril 6–8 times daily (before use, warm the required dose in a syringe [use syringe without needle] to body temperature; store the remaining solution in the refrigerator, avoiding bacterial contamination).

Acute and recurrent pneumonia of viral and viral-bacterial etiology:

• Administer Alfarekin® intramuscularly 1 million IU for 5–7 days in combination with comprehensive treatment (antibacterial, detoxification, anti-inflammatory, etc.).

Acute diarrheal syndrome in newborns:

• Administer rectally as daily micro-enemas containing 100,000 IU of Alfarekin® for 3–7 days.

Purulent-septic diseases, peritonitis, multiple abdominal abscesses:

• Administer intravenously 2–4 million IU once daily; total course dose 12–16 million IU. Simultaneous endolymphatic administration of the drug at the same dose (2–4 million IU once daily) may also be indicated.

Herpes infections:

• Zoster (shingles): daily intramuscular injection of 1 million IU + 2 million IU in 5 mL of 0.9% sodium chloride solution administered subcutaneously at multiple points around the rash area. Treatment duration: 5–7 days;
• Skin herpes lesions: daily intramuscular or subcutaneous (around the lesion) administration of 2 million IU; treatment may be combined with local application (compresses) to herpes papules; treatment duration determined by physician;
• Genital herpes infection: daily intramuscular administration of 2 million IU in combination with local application of the drug as compresses over the rash areas; treatment duration determined by physician;
• Herpetic keratoconjunctivitis: administer Alfarekin® solution – 1 million IU in 5 mL of 0.9% sodium chloride solution – subconjunctivally, 2–3 drops every 2 hours for 7–10 days; once symptoms subside, administer every 4 hours; treatment duration determined by physician;
• Acute herpetic stomatitis in children: 250,000 IU per dose, 4 times daily as local compresses in combination with intranasal administration. Dilute Alfarekin® 1 million IU in 4 mL of water for injection; use 1 mL of solution per application and intranasal administration: 2 drops administered intranasally, the remainder applied locally as compresses after hygienic cleaning of the oral mucosa. Treatment course: 7–10 days.

Chronic urogenital chlamydia:

Treatment of urogenital chlamydia is conducted in two stages:

• Stage 1 – preparatory, including use of enterosorbents and polyvitamin preparations at therapeutic doses for 2 weeks. From day 10, the immunotropic agent thymalin is administered at 10 mg intramuscularly in the evening every other day; total course – 5 injections;
• Stage 2 – main stage, involving basic antibacterial therapy as follows: first antibiotic for 5 days; after a 7-day break, a second antibiotic is prescribed for 10 days. During the break and after completion of antibacterial therapy, Alfarekin® is administered at 1 million IU intramuscularly once daily in the evening; total course – 10 injections.

During antibacterial therapy, antifungal agents (nystatin, fluconazole, clotrimazole, ketoconazole) and hepatoprotectors (carsil) should be used at therapeutic doses.

Neurological disorders with mono- and polyradicular pain syndromes:

• Administer intramuscularly at 1 million IU daily for 5–10 days as part of comprehensive treatment.

Laryngeal papillomatosis:

• Subcutaneous administration of 3 million IU/m² three times weekly (every other day) for 6 months or longer; adjust dose according to tolerability. Begin treatment after surgical (laser) removal of tumor tissue.

Multiple sclerosis:

• Administer intramuscularly 1 million IU 2–3 times daily for 10–15 days, followed by weekly administration of 1 million IU for 6 months.

Cutaneous melanoma:

• As adjunct to surgical treatment and for induction of remission: intravenous infusion of 20 million IU/m² (infusion over 20 minutes), 5 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), elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (exceeding upper normal limit by 5 times), discontinue the drug until parameters normalize. Resume treatment at half dose. If intolerance persists and granulocyte count drops to 250/mm³ or ALT and/or AST activity increases (exceeding upper normal limit by 10 times), discontinue the drug.

Uveal melanoma:

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

Kaposi’s sarcoma: possible treatment regimens:

• Intramuscular administration daily for 10 days at 3 million IU per injection; treatment combined with monotherapy using prosidin; repeat courses – once monthly for 6 months;
• Intravenous infusion over 30 minutes at 50 million IU (30 million IU/m²) daily for 5 days or with 1-day intervals, followed by a minimum 9-day break before starting a new 5-day course; treatment duration determined by physician.

Multiple myeloma:

• Intramuscular administration daily for 10 days at 3 million IU per injection; repeat courses – once every 1.5–3 months (4–6 times per year).

Chronic myeloid leukemia:

• Subcutaneous administration at 3 million IU/m² daily or every other day, gradually increasing 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:

• Intramuscular administration of 3 million IU three times weekly (every other day) for 4–6 weeks. After achieving remission, maintenance therapy is administered at 3 million IU every other day for up to 12 months.

Non-Hodgkin’s malignant lymphomas, specifically follicular lymphoma:

• Intramuscular administration of 3 million IU three times weekly for 12–18 months as maintenance therapy after achieving remission induced by chemotherapy. In cases of partial remission, other chemotherapy protocols are indicated, followed by Alfarekin® therapy at 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 injection as solvent (when preparing solution for subcutaneous, intradermal, or intramuscular administration). To prepare the solution, dissolve the vial contents in 1 mL of water for injection.

Preparation and administration of intravenous infusion.

Begin infusion of 0.9% sodium chloride solution (at 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 injection (1 mL of water per dose to be administered), then withdraw the required amount and add to 50 mL of 0.9% sodium chloride solution; administer the prepared solution intravenously by drip infusion over 30 minutes. After completing Alfarekin® infusion, continue infusion of 0.9% sodium chloride solution at 200 mL/hour for 10 minutes.

The injectable solution should be used immediately. For intranasal use, the solution may be used within 24 hours if stored at 2–8°C.

Children.

Use in pediatric practice for acute respiratory viral infection in children, including newborns; acute diarrheal syndrome in newborns; acute herpetic stomatitis in children (see section "Administration and Dosage").

Overdose.

No cases of overdose with Alfarekin® have been reported to date. However, as with any drug overdose, symptomatic therapy is recommended, with monitoring of vital organ functions and careful observation of the patient's condition.

Adverse Reactions

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

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

Subcutaneous administration of Alfarekin®, as with all other alpha interferon products, is usually accompanied by a flu-like syndrome characterized by fever, chills, headache, muscle and joint pain, lethargy, and malaise. These adverse effects, which are mild to moderate in severity and dose-dependent, typically occur only during the first days of treatment and then gradually diminish and resolve. These symptoms can be controlled or significantly reduced by administering paracetamol (acetaminophen) at a dose of 0.5–1 g 30–40 minutes before injection. Vomiting, dizziness, and flushing are less common.

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 HCV and HBV.

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

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

Immune system disorders**, including sarcoidosis, sarcoidosis flare-up, 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, anxiety, 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, flushing, difficulty concentrating, somnolence, taste disturbances, peripheral neuropathy, cerebral hemorrhage, cerebrovascular ischemia, seizures, disturbance of consciousness 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 swelling, 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 mucosa 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 ulcerative-gangrenous stomatitis, right upper quadrant abdominal pain, dyspepsia, glossitis, gastroesophageal reflux, gingivitis, constipation, diarrhea, pancreatitis, ischemic colitis, ulcerative colitis, gum 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 muscle 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 test abnormalities, including weight loss, decreased growth parameters (reduced growth 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 Warnings and Precautions for Use".

*** See below for information on pulmonary arterial hypertension.

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

Cardiovascular adverse effects, particularly arrhythmias, are primarily associated with pre-existing cardiovascular disease and occur after therapy with cardiotoxic agents. Reversible cardiomyopathy has been rarely observed in patients without prior symptoms of heart disease after initiation of interferon alfa therapy.

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

A wide range of autoimmune and immune-mediated disorders have been observed with 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 occurring more frequently at doses exceeding 10 million IU per day include decreased granulocyte and leukocyte counts; decreased hemoglobin and platelet counts; increased serum alkaline phosphatase, LDH, serum creatinine, and blood urea nitrogen levels. Moderate, usually reversible, pancytopenia has also been observed. Elevations in ALT/AST levels above normal have been observed in some non-hepatitis C patients, as well as in some patients with chronic hepatitis B, coinciding with viral DNA polymerase clearance.

The adverse reaction profile in children and adolescents is generally similar to that in adults, although there is a specific pediatric concern regarding growth suppression. 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 occur more frequently in children and adolescents than in adult patients.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at 2 to 8°C, out of reach of children.

Packaging. Lyophilisate for solution for injection: 1 million IU or 3 million IU in vials;
10 vials of lyophilisate (1 million IU or 3 million IU) per carton;
5 vials of lyophilisate (1 million IU or 3 million IU) and 5 ampoules of solvent (water for injection) 2 ml each per carton;
1 vial of lyophilisate (1 million IU or 3 million IU) and 1 ampoule of solvent (water for injection) 2 ml per carton.

Prescription status. Prescription only.

Manufacturer. LLC "Scientific-Production Company "Interfarmbiotek".

LLC "VALARTIN PHARMA".

Manufacturer's address and place of business.

Ukraine, 03143, Kyiv, Zabolotnoho St., 150.

Ukraine, 08135, Chayky village, Kyiv-Sviatoshynskyi district, Kyiv region, Grushevskoho St., 60.

Marketing Authorization Holder. LLC "VALARTIN PHARMA", Ukraine.

Address of Marketing Authorization Holder.

Ukraine, 08135, Chayky village, Kyiv-Sviatoshynskyi district, Kyiv region, Grushevskoho St., 60.