Betfer 1a plus

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BETFER 1a PLUS (Betfer 1a PLUS)

Composition:

Active substance: interferon beta-1a;

1 vial contains 30 mcg (6,000,000 IU) of recombinant human interferon beta-1a;

Excipients: human albumin 20%, disodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride;

Solvent: sterile water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or slightly creamy-colored powder, free from foreign particulate matter.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunostimulants. Interferons. Interferon beta-1a. ATC code L03AB07.

Pharmacological Properties

Pharmacodynamics

Interferons are natural proteins produced by eukaryotic cells in response to viral infection and the action of other biological factors. Interferons are cytokines that act as mediators of the body's antiviral, antiproliferative, and immunomodulatory systems.

Beta-interferon is synthesized by various cell types, including fibroblasts and macrophages. Natural interferon and the medicinal product Betfer 1a PLUS (interferon beta-1a) exist in a glycosylated form and contain a single complex carbohydrate moiety linked to a nitrogen atom. Glycosylation of proteins affects their stability, activity, distribution, and half-life.

The biological properties of Betfer 1a PLUS are determined by the ability of interferon beta-1a to bind to specific receptors on the cell surface. This binding initiates a complex cascade of intracellular interactions, leading to interferon-induced expression of numerous gene products and markers, including major histocompatibility complex class I, Mx protein, 2'/5'-oligoadenylate synthetase, beta2-microglobulin, and neopterin.

The relationship between the mechanism of action of Betfer 1a PLUS in the treatment of multiple sclerosis and the initiation of the biological interactions described above is not fully understood, as the pathophysiology of multiple sclerosis is not completely elucidated.

Pharmacokinetics

The pharmacokinetic characteristics of interferon beta-1a were studied based on measurements of interferon antiviral activity.

After a single intramuscular injection of interferon beta-1a, peak levels of antiviral activity are reached between 5 and 15 hours. The elimination half-life is approximately 10 hours. Bioavailability is approximately 40%. The bioavailability of interferon beta-1a following intramuscular administration is 3 times higher than after subcutaneous administration.

Clinical characteristics.

Indications.

• Relapsing-remitting (disseminated) multiple sclerosis characterized by at least two relapses within the previous three years and absence of signs of continuous progressive course between relapses.
• Demyelination due to active inflammatory process requiring intravenous administration of corticosteroids, except for diagnoses other than multiple sclerosis, as well as presence of a high risk of developing clinically evident multiple sclerosis.

Contraindications.

Hypersensitivity to natural or recombinant interferon beta, human serum albumin, or any component of the drug; severe depression; suicidal tendencies; epilepsy without effective adequate therapy.

Interaction with other medicinal products and other types of interactions.

Interferons are known to reduce the activity of cytochrome P450 enzyme system. Caution should be exercised when using Betfer 1a PLUS with drugs having a narrow therapeutic index and whose clearance is highly dependent on cytochrome P450, for example, antiepileptic drugs and antidepressants.

Concomitant use of the drug with corticosteroids or adrenocorticotropic hormone (ACTH) preparations has not been studied; however, results of clinical trials indicate that patients with multiple sclerosis may receive the drug in combination with glucocorticosteroids (GCS) or ACTH during disease relapses. Incompatible with myelosuppressive drugs.

Special precautions for use.

Betfer 1a PLUS should be used with caution in patients with depression or a history of depressive disorders. It is known that interferon therapy may lead to the development of depressive conditions and suicidal ideation; in patients with multiple sclerosis, the frequency of these events is increased. In isolated cases, these conditions may lead to suicide attempts. Patients should be informed about this risk and advised to seek immediate medical attention if any symptoms of depression and/or suicidal thoughts occur. Such patients require close monitoring throughout treatment, and appropriate therapeutic interventions should be initiated if necessary. In some cases, discontinuation of Betfer 1a PLUS may be required.

The drug should be used cautiously in patients who have previously experienced seizures or who are receiving antiepileptic medications. If seizures occur for the first time during treatment with the drug, their etiology should be evaluated, and anticonvulsant therapy should be initiated before resuming interferon beta-1a treatment.

Patients with cardiovascular disorders, such as ischemic heart disease, angina pectoris, congestive heart failure, or arrhythmias, should be closely monitored clinically and through laboratory tests, and their condition should be carefully followed during therapy with Betfer 1a PLUS. Flu-like symptoms associated with drug administration may induce stress in such patients.

The drug should be administered with caution and under close medical supervision in patients with severe renal or hepatic impairment, as well as in those with marked bone marrow suppression.

Liver function abnormalities, including elevated serum liver enzymes, hepatitis, autoimmune hepatitis, and liver failure, have been reported during interferon beta therapy. Patients should be closely monitored for signs of liver dysfunction, especially when concomitant use with hepatotoxic drugs is required. The potential for enhanced effects when used concomitantly with other medicinal products or substances having hepatotoxic effects (e.g., alcohol) has not been studied.

Cases of nephrotic syndrome have been reported during treatment with interferon beta-1a, resulting from various nephropathies, including collapsing focal segmental glomerulosclerosis, minimal change nephropathy, membranoproliferative glomerulonephritis, and membranous nephropathy. These cases occurred at varying intervals during treatment, even several years after initiation of therapy.

Regular monitoring for early signs and symptoms such as edema, proteinuria, and impaired kidney function is recommended during treatment, particularly in patients at high risk for kidney disease. If nephrotic syndrome develops, appropriate treatment should be initiated immediately, and discontinuation of the drug should be considered. The drug should be used with caution in patients with renal impairment or severe myelosuppression.

Patients with a history of thyroid disorders should have regular thyroid function tests; in other cases, testing should be performed based on clinical indications.

There are only limited data on the safety and efficacy of the drug in non-ambulatory patients with multiple sclerosis. The use of the drug has not been studied in patients with primary progressive multiple sclerosis, and therefore it should not be used for the treatment of such patients.

Severe hypersensitivity reactions (rare, but sometimes acute and severe, such as bronchospasm, anaphylaxis, and urticaria) may occur.

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), have been reported, some of which were fatal. Therefore, careful monitoring for early symptoms of these conditions—such as hypertension, thrombocytopenia, and impaired renal function—is recommended during treatment. If TTP or HUS develops, treatment should be initiated immediately and administration of the drug should be discontinued.

Local necrosis at the injection site may occur during treatment. To reduce the risk, the injection site should be rotated regularly and aseptic techniques strictly followed. Self-administration by patients should be periodically reviewed, especially if local reactions occur. Administration of the drug should be discontinued in cases of multiple skin lesions until healing occurs. Patients with isolated lesions may continue treatment if the necrotic area is small.

Patients should be informed about the potential of interferon beta-1a to induce abortions. Effective contraception is required during treatment.

During therapy, it is recommended to monitor white blood cell and platelet counts, differential blood count, and biochemical parameters, particularly liver function tests, at months 1, 3, and 6 of treatment.

Laboratory abnormalities may occur during interferon therapy; therefore, in addition to routine monitoring in patients with multiple sclerosis, regular monitoring of blood cell counts (particularly platelets), differential blood count, and liver function tests, including liver enzymes, is recommended. Patients showing signs of bone marrow suppression may require more frequent blood monitoring.

With prolonged use (more than 12 months) of Betfer 1a PLUS, neutralizing antibodies may develop in 4–8% of patients, which reduce the activity of interferon beta-1a and thereby diminish the clinical efficacy of the drug.

This medicinal product contains 0.15 mmol (or 3.48 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding. Contraindicated.

Effect on ability to drive or operate machinery.

The effect of Betfer 1a PLUS on the ability to drive or operate machinery has not been studied. Some adverse reactions affecting the central nervous system may impair the ability to drive or operate complex machinery.

Method of Administration and Dosage

Treatment with the drug should be initiated under careful medical supervision by a physician experienced in managing such diseases.

Adults. The recommended dose is 30 mcg (1 mL of prepared solution) once weekly. The drug should be administered intramuscularly.

An increase in therapeutic effect with administration of higher doses (60 mcg) once weekly has not been confirmed.

The site of intramuscular injection should be changed each week.

Patients are recommended to take an analgesic-antipyretic agent before administration of the drug and for 24 hours after its administration to reduce flu-like symptoms caused by the administration of Betfer 1a PLUS. These symptoms usually occur during the first months of therapy.

The duration of treatment has not been definitively established and is determined individually.

After two years of treatment, the patient should undergo a clinical examination and continue therapy based on individual physician's recommendation.

Treatment should be discontinued in case of development of chronic progressive multiple sclerosis.

If possible, injections should be administered at the same time and on the same day each week.

The use of any other diluent is not permitted.

After reconstitution, the appearance of the reconstituted solution should be inspected. The drug must not be used if an insoluble precipitate is present or if there is a change in color (a faint yellow tint is acceptable).

After preparation, the reconstituted solution should be administered immediately by intramuscular injection using a syringe (1 mL).

If a patient receives less than the full dose, the remaining drug must be discarded.

Elderly patients. Clinical studies did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, based on pharmacokinetic data, elderly patients do not require dose adjustment.

Children. The efficacy and safety of use in children have not been studied; therefore, the drug should not be prescribed to patients in this age group.

Overdose. Cases of overdose are unknown. In case of overdose, medical attention should be sought for observation and timely symptomatic therapy.

Adverse reactions.

Flu-like symptoms: headache, nausea, muscle pain, joint pain, back pain, limb pain, arthralgia, myasthenia, increased sweating, malaise, chills, general weakness.

Gastrointestinal disorders: constipation, diarrhea, vomiting, nausea, loss of appetite, abdominal pain, anorexia, weight gain/weight loss, hepatitis with or without jaundice, hepatic failure, autoimmune hepatitis. Interferon beta may potentially cause severe liver injury. The mechanism of development of this rare dysfunction accompanied by clinical manifestations has not yet been studied. Most cases of severe liver injury occurred within the first 6 months of treatment. Specific risk factors for the development of this condition have not been established. If jaundice or other clinical signs of liver dysfunction occur, treatment with the drug should be discontinued.

Psychiatric disorders: depression, insomnia; suicide attempts.

Central nervous system (CNS) disorders: headache, transient neurological symptoms (such as hypoesthesia, muscle spasms, paresthesia, difficulty in walking, musculoskeletal stiffness), which may resemble exacerbation of multiple sclerosis, dizziness, restlessness, insomnia, migraine, coordination disorders, dizziness, anxiety, in individual cases – depression, suicidal tendencies, depersonalization, seizures, insomnia, emotional lability, neurotic symptoms, syncope³, paresthesia, anxiety sensations, insomnia, psychosis, headache, confusion.

Cardiovascular system disorders: vasodilation, arrhythmia, hypertension, capillary leak syndrome in patients with a history of monoclonal gammopathy, palpitations, cardiomyopathy, congestive heart failure, palpitations, tachycardia, hot flushes.

Blood and laboratory parameters: possible neutropenia, anemia, thrombotic microangiopathy including thrombotic thrombocytopenic purpura, hemolytic uremic syndrome (characteristic of the class of beta-interferon drugs, see section "Special precautions for use"), pancytopenia, thromboembolic complications. Increased formation of autoantibodies, elevated levels of potassium, blood urea nitrogen, decreased hematocrit, lymphocyte, leukocyte, and neutrophil counts in blood. Increased blood bilirubin levels, hypoglycemia. Hypersensitivity reactions may occur, changes in laboratory test parameters (leukopenia, lymphopenia, thrombocytopenia, elevated AST, ALT, γ-glutamyl transferase, and alkaline phosphatase). These changes are usually mild, reversible, and asymptomatic.

Eye disorders: retinal vascular disorders (e.g., retinopathy, "cotton wool" spots on retina, retinal artery or vein occlusion), visual disturbances, conjunctivitis.

Local and skin reactions: itching, rash, urticaria, angioedema, erythema multiforme, skin reactions resembling polymorphic exudative erythema, Stevens-Johnson syndrome, injection site inflammation, injection site abscess, subcutaneous fat tissue inflammation at injection site, skin pigmentation disorders or skin hyperemia, skin atrophy at injection site, erythematous or maculopapular rash, skin hyperemia, vesicular rash, alopecia, skin pallor, exacerbation of psoriasis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia, drug-induced lupus erythematosus, muscle cramps, neck and back pain, limb pain, muscle rigidity, muscle pain, arthritis.

Injection site reactions: inflammation at injection site, redness, swelling, induration, skin pallor, pain, flu-like symptoms, pain/erythema/bruising at injection site, weakness, chills, fever, burning sensation at injection site, abscess at injection site, increased sweating, subcutaneous fat tissue inflammation at injection site, bleeding at injection site, very rarely – necrosis at injection site, which usually does not require discontinuation of the drug or additional treatment.

Systemic manifestations: anaphylactic reactions, drug-induced lupus erythematosus, infections, Stevens-Johnson syndrome.

Effects characteristic of the class of beta-interferon drugs

During treatment with interferons, anorexia, dizziness, development of anxiety, arrhythmia, vasodilation, and palpitations may be observed.

During treatment with beta-interferon, increased formation of autoantibodies may occur.

Respiratory system disorders: dyspnea, pulmonary arterial hypertension (characteristic of the class of beta-interferon drugs, see below on pulmonary arterial hypertension), upper respiratory tract infections, cough, dyspnea, chest pain, bronchospasm, rhinorrhea.

Urinary and reproductive system disorders: nephrotic syndrome, hemolytic uremic syndrome, nephrotic sclerosis, glomerulosclerosis, menorrhagia, metrorrhagia, urinary retention/incontinence, proteinuria, imperative urges to urinate, dysmenorrhea, impotence, peripheral edema.

Disorders of the reproductive system and mammary glands: menorrhagia, metrorrhagia, dysmenorrhea, impotence.

Aural disorders: ear pain, sinusitis.

Endocrine disorders: thyroid function disorders (hypothyroidism or hyperthyroidism) may occur.

Hepatobiliary disorders:

asymptomatic increase in transaminase levels; marked increase in transaminase levels; hepatitis with or without jaundice; hepatic failure (see section "Special precautions for use"), autoimmune hepatitis.

Other disorders: alopecia rarely observed.

Pulmonary arterial hypertension

Cases of pulmonary arterial hypertension have been reported during treatment with beta-interferon drugs. Such cases occurred after varying intervals, even several years after initiation of treatment.

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of medicinal products is of major importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the National Reporting System (Automated Pharmacovigilance Information System).

Shelf life.

2 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature of 2 °C to 8 °C.

Keep out of reach of children.

Incompatibility

The drug is incompatible with myelosuppressive agents.

Packaging. 30 mcg (6,000,000 IU) per vial, supplied with solvent: water for injections, 1 ml in an ampoule. 1 or 4 sets per blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer: LLC "FZ “STADA”.

Manufacturer's address and location of its business activity:

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