Extavia (Lyophilisate) Instructions for Use

ATC Code

L03AB08 (Interferon beta-1b)

Active Substance

Interferon beta-1b

Interferon beta-1b

Clinical-Pharmacological Group

Interferon. A drug used for multiple sclerosis

Pharmacotherapeutic Group

MIBP-cytokine

Pharmacological Action

Interferon beta-1b, used for multiple sclerosis (MS), has antiviral and immunoregulatory activity. The mechanisms of action of interferon beta-1b in multiple sclerosis have not been fully established. However, it is known that the biological effect of interferon beta-1b is mediated by its interaction with specific receptors found on the surface of human cells.

Binding of interferon beta-1b to these receptors induces the expression of a number of substances that are considered as mediators of the biological effects of interferon beta-1b. The content of some of these substances was determined in the serum and blood cell fractions of patients treated with Interferon beta-1b. Interferon beta-1b reduces the binding capacity and expression of gamma-interferon receptors and enhances their degradation. The drug increases the suppressor activity of peripheral blood mononuclear cells.

In both relapsing-remitting and secondary-progressive multiple sclerosis, treatment with interferon beta-1b reduces the frequency (by 30%) and severity of clinical exacerbations of the disease, the number of hospitalizations and the need for steroid treatment, and also prolongs the duration of remission.

In patients with secondary-progressive multiple sclerosis, the use of interferon beta-1b delays the further progression of the disease and the onset of disability (including severe disability, when patients are forced to use a wheelchair permanently) for up to 12 months. This effect is observed in patients both with and without disease exacerbations, and with any disability index (the study included patients with a score of 3.0 to 6.5 points on the Expanded Disability Status Scale EDSS).

Magnetic resonance imaging (MRI) results of the brain in patients with relapsing-remitting and secondary-progressive multiple sclerosis against the background of treatment with interferon beta-1b showed a significant positive effect of the drug on the severity of the pathological process, as well as a significant reduction in the formation of new active lesions.

Pharmacokinetics

After subcutaneous administration of interferon beta-1b at the recommended dose of 0.25 mg, serum concentrations of the drug are low or not detectable at all. In this regard, there is no information on the pharmacokinetics of the drug in patients with multiple sclerosis receiving Interferon beta-1b at the recommended dose.

After subcutaneous administration of 0.5 mg of the drug, C_max in plasma is reached 1-8 hours after injection and is about 40 IU/ml. The absolute bioavailability after subcutaneous administration is about 50%.

With intravenous use of interferon beta-1b, the clearance and T_1/2 of the drug from serum are on average 30 ml/min/kg and 5 hours, respectively.

Administration of interferon beta-1b every other day does not lead to an increase in the serum concentration of the drug, and its pharmacokinetics do not change during the course of therapy.

With subcutaneous administration of interferon beta-1b at a dose of 0.25 mg every other day, the levels of biological response markers (neopterin, beta 2-microglobulin and the immunosuppressive cytokine interleukin) significantly increased compared to baseline 6-12 hours after the first dose. They peaked at 40-124 hours and remained elevated throughout the 7-day (168-hour) study period.

Indications

• relapsing-remitting multiple sclerosis (RRMS) – to reduce the frequency and severity of exacerbations in outpatients (i.e., patients able to walk without assistance) with a history of two or more exacerbations of the disease in the last 2 years with subsequent complete or incomplete recovery of neurological deficit;
• secondary-progressive multiple sclerosis with active disease, characterized by exacerbations or significant deterioration of neurological functions over the past two years – to reduce the frequency and severity of clinical exacerbations of the disease, as well as to slow the rate of disease progression.

ICD codes

Dosage Regimen

Lyophilisate

Treatment with Extavia should be initiated under the supervision of a physician experienced in the treatment of this disease.

The question of the duration of treatment with Extavia remains unresolved. In clinical studies, the duration of therapy in patients with relapsing-remitting and secondary-progressive multiple sclerosis reached 5 years and 3 years, respectively. The duration of the course is determined by the doctor.

Preparation of the injection solution

To dissolve the lyophilized interferon beta-1b powder for injection, use the supplied ready-to-use syringe with solvent and needle. 1.2 ml of solvent (0.54% sodium chloride solution) is injected into the vial with Extavia. The powder should dissolve completely without shaking. The finished solution should be inspected before use. If particles are present or the color of the solution has changed, it should not be used. 1 ml of the finished solution contains 0.25 mg (8 million IU) of interferon beta-1b.

The drug should be administered subcutaneously immediately after preparation of the solution. If the injection is delayed, the solution should be stored in the refrigerator and used within 3 hours. The solution must not be frozen.

Method of administration

Subcutaneously

Dosage

The recommended dose of Extavia is 0.25 mg (8 million IU), which is contained in 1 ml of the prepared solution, administered subcutaneously every other day.

If you forget to give yourself an injection at the scheduled time, you should administer the drug as soon as you remember. The next injection is given 48 hours later.

Adverse Reactions

Flu-like symptoms can be alleviated by using non-steroidal anti-inflammatory drugs.

Experience with the use of the drug for the treatment of patients with multiple sclerosis is quite limited, therefore, adverse reactions occurring with low frequency may not yet have been observed.

The most appropriate term from the Medical Dictionary for Regulatory Activities (MedDRA) is used to describe a specific reaction, its synonyms and related conditions.

Below are the adverse events observed with a frequency of 2% or more higher than in the placebo group in patients who received the drug at a dose of 0.25 mg/m² or 0.16 mg/m² every other day for up to 3 years in controlled clinical studies.

General disorders and administration site conditions injection site reactions (including hemorrhage, hypersensitivity reactions, inflammation, swelling, pain, irritation, edema, injection site atrophy), asthenia, flu-like symptom complex (includes flu symptoms and/or a combination of at least two of the following adverse events: fever, chills, myalgia, malaise, increased sweating), pain in various locations, increased body temperature, chills, peripheral edema, chest pain, malaise, injection site necrosis.

Cardiovascular system disorders arterial hypertension.

Digestive system disorders abdominal pain.

Hepatobiliary system disorders increase in ALT level more than 5 times compared to baseline, increase in AST level more than 5 times compared to baseline.

Blood and lymphatic system disorders lymphopenia (<1500/mm³), absolute neutropenia (<1500/mm³), leukopenia (<3000/mm³), lymphadenopathy.

Musculoskeletal system disorders muscle hypertonia, myalgia, myasthenia, back and limb pain, leg cramps.

Central and peripheral nervous system disorders headache, dizziness, insomnia, migraine, paresthesia, coordination disturbances.

Special senses disorders conjunctivitis, vision disturbance, ear pain.

Respiratory system disorders dyspnea.

Dermatological reactions skin reactions, rash.

Urinary and reproductive system disorders urinary urgency, in premenopausal women – metrorrhagia (acyclic bleeding), in men – impotence.

During therapy with interferon beta-1b in clinical practice, regardless of the presence of a causal relationship with the use of the drug, the following adverse events were noted. The frequency of adverse events was assessed as follows: occurring “very commonly” (>1/10), “commonly” (>1/100; <1/10), “uncommonly” (>1/1000; <1/100), “rarely” (≥1/10000; <1/1000), “very rarely” (<1/10000).

General disorders and administration site conditions very common – flu-like symptom complex*, chills*, increased body temperature*, injection site reactions*, injection site inflammation*, injection site pain; common – injection site necrosis*; rare – chest pain, malaise, increased sweating, increase or decrease in body weight. The frequency of flu-like syndrome decreases over time.

Blood and lymphatic system disorders uncommon – anemia, thrombocytopenia, leukopenia; rare – lymphadenopathy.

Endocrine system disorders rare – hyperthyroidism, hypothyroidism, thyroid dysfunction.

Metabolic and nutritional disorders rare – hypertriglyceridemia.

Central and peripheral nervous system disorders rare – convulsions, dizziness.

Psychiatric disorders uncommon — depression; rare – confusion, agitation, emotional lability, suicide attempts, anorexia.

Cardiovascular system disorders uncommon – arterial hypertension; rare – cardiomyopathy, tachycardia, palpitations; very rare – vasodilation.

Respiratory system disorders rare – bronchospasm, dyspnea.

Digestive system disorders uncommon – nausea, vomiting; rare – pancreatitis, diarrhea.

Hepatobiliary system disorders uncommon – increased AST and ALT activity; rare – hyperbilirubinemia, increased gamma-glutamyltransferase (γ-GT) activity, hepatitis.

Dermatological reactions uncommon – urticaria, rash, pruritus, alopecia; rare – skin discoloration.

Musculoskeletal system disorders uncommon – myalgia, muscle hypertonia, arthralgia.

Female reproductive system disorders rare – menstrual cycle disorder; very rare – menorrhagia (prolonged menstrual bleeding).

Allergic and immunopathological reactions rare – anaphylactic reactions.

*frequency of these AEs is indicated according to clinical trial data

Contraindications

• Severe forms of depression and/or suicidal thoughts (including in history);
• Decompensated liver disease;
• Pregnancy and breastfeeding;
• Hypersensitivity to natural or recombinant beta-interferon or human albumin or any other component of the drug.

With caution

• Heart disease, in particular, heart failure stage III-IV according to the New York Heart Association (NYHA) classification, cardiomyopathy;
• Monoclonal gammopathy;
• Anemia, thrombocytopenia, leukopenia;
• Impaired liver function;
• History of epileptic seizures;
• Severe renal impairment.

Due to the lack of sufficient experience with use, caution is required when using the drug in patients under 18 years of age.

Use in Pregnancy and Lactation

Pregnancy

It is not known whether the drug can cause fetal harm when administered to pregnant women or affect human reproduction. In controlled clinical trials in patients with multiple sclerosis, cases of spontaneous abortion have been reported. In studies in rhesus monkeys, human Interferon beta-1b had an embryotoxic effect and at higher doses caused an increase in the frequency of abortions. Women of childbearing potential should use reliable methods of contraception while being treated with this drug. If pregnancy occurs during treatment with Extavia or if pregnancy is planned, it is recommended to discontinue the drug.

Lactation

It is not known whether Interferon beta-1b is excreted in breast milk. Given the theoretical possibility of adverse reactions in breastfed infants, breastfeeding should be discontinued or the drug should be discontinued.

Use in Hepatic Impairment

Contraindicated in decompensated liver disease.

Use with caution in impaired liver function.

When treating with Extavia, liver function should be monitored (including assessment of the clinical picture). An increase in serum transaminase levels requires careful observation and examination. If serum transaminases are significantly increased or signs of liver damage (e.g., jaundice) appear, the drug should be discontinued. In the absence of clinical signs of liver damage or after normalization of liver enzyme levels, therapy with Extavia may be resumed with monitoring of liver function.

Use in Renal Impairment

Use with caution in severe renal impairment.

Pediatric Use

Use with caution in children and adolescents under 18 years of age.

Special Precautions

The drug contains human albumin, and for this reason there is a very small risk of transmission of viral diseases. The theoretical risk of transmission of Creutzfeldt-Jakob disease is also considered extremely unlikely.

Changes in laboratory parameters

In addition to the standard laboratory tests prescribed for the management of patients with multiple sclerosis, before starting therapy with Extavia, and also regularly during treatment, it is recommended to perform a complete blood count, including differential white blood cell count, platelet count and blood chemistry, and to check liver function (e.g., AST, ALT and γ-GT activity). In the management of patients with anemia, thrombocytopenia, leukopenia (separately or in combination), more careful monitoring of the complete blood count, including red blood cell count, white blood cell count, platelet count and differential white blood cell count, may be required.

Gastrointestinal disorders

In rare cases, the development of pancreatitis has been observed during treatment with Extavia, in most cases associated with the presence of hypertriglyceridemia.

Liver and biliary tract disorders

Clinical studies have shown that therapy with Extavia can often lead to asymptomatic increases in liver transaminases, which in most cases are mild and transient.

As with treatment with other beta-interferons, severe liver damage (including liver failure) with the use of Extavia is rare. The most severe cases were observed in patients exposed to hepatotoxic drugs or substances, as well as in some concomitant diseases (e.g., malignant diseases with metastases, severe infections and sepsis, alcohol abuse).

When treating with Extavia, liver function should be monitored (including assessment of the clinical picture). An increase in serum transaminase levels requires careful observation and examination. If serum transaminases are significantly increased or signs of liver damage (e.g., jaundice) appear, the drug should be discontinued. In the absence of clinical signs of liver damage or after normalization of liver enzyme levels, therapy with Extavia may be resumed with monitoring of liver function.

Endocrine disorders

Patients with thyroid dysfunction are recommended to have regular thyroid function checks (thyroid hormones, thyroid-stimulating hormone), and in other cases – as clinically indicated.

Cardiovascular diseases

Extavia should be used with caution in patients with heart disease, in particular, heart failure stage III-IV according to the New York Heart Association (NYHA) classification, since such patients were not included in clinical studies.

If cardiomyopathy develops during treatment with Extavia and is suspected to be associated with the use of the drug, then treatment with Extavia should be discontinued.

Nervous system diseases

Patients should be informed that depression and suicidal thoughts may be a side effect of Extavia, and if they occur, they should consult a doctor immediately.

In two controlled clinical trials involving 1657 patients with secondary-progressive multiple sclerosis, no significant differences in the frequency of depression and suicidal thoughts were found with the use of Extavia or placebo. Nevertheless, caution should be exercised when prescribing Extavia to patients with a history of depressive disorders and suicidal thoughts. If such phenomena occur during treatment, the advisability of discontinuing the drug should be considered.

Extavia should be used with caution in patients with a history of epileptic seizures.

General disorders and injection site reactions

Serious allergic reactions may occur (rare, but acute and severe, such as bronchospasm, anaphylaxis and urticaria).

If signs of skin integrity damage appear (e.g., fluid discharge from the injection site), the patient should consult a doctor before continuing to administer Extavia injections.

Cases of injection site necrosis have been observed in patients receiving Extavia. Necrosis can be extensive and extend to muscle fascia, as well as adipose tissue and, as a result, lead to scarring. In some cases, removal of necrotic areas or, less commonly, skin grafting is required. The healing process can take up to 6 months.

If multiple foci of necrosis appear, treatment with Extavia should be discontinued until the damaged areas are completely healed. If there is a single focus, if the necrosis is not too extensive, the use of Extavia may be continued, since in some patients healing of the necrotic area at the injection site occurred while using the drug.

To reduce the risk of injection site reaction and necrosis, patients should be advised

• to perform injections strictly following aseptic technique rules

• to change the injection site each time

• to administer the drug strictly subcutaneously

The correctness of self-injections should be periodically monitored, especially if local reactions occur.

Neutralizing Antibodies

As with treatment with any other protein-containing drugs, there is a possibility of antibody formation when using Extavia. In a number of controlled clinical trials, serum was analyzed every 3 months to detect the development of antibodies to interferon beta-1b.

These studies showed that neutralizing antibodies to interferon beta-1b developed in 23-41% of patients, confirmed by at least two subsequent positive laboratory test results. In 43-55% of these patients, subsequent laboratory tests revealed a stable absence of antibodies to interferon beta-1b.

It has not been proven that the presence of neutralizing antibodies has any significant impact on clinical outcomes, including MRI data. The development of neutralizing activity was not associated with the occurrence of any adverse reactions.

The decision to continue or discontinue therapy should be based on clinical disease activity indicators, not on neutralizing activity status.

Immune Disorders

The use of cytokines in patients with monoclonal gammopathy has sometimes been accompanied by a systemic increase in capillary permeability leading to shock and death.

Effect on Ability to Drive and Operate Machinery

Special studies have not been conducted. Adverse reactions from the CNS may affect the ability to drive a car and operate machinery. Therefore, caution should be exercised when engaging in potentially hazardous activities requiring increased attention.

Overdose

No serious adverse events were identified when interferon beta-1b was administered intravenously at a dose of up to 5.5 mg (176 million IU) three times a week to adult patients with cancer.

Drug Interactions

Special studies of the interaction of Extavia with other drugs have not been conducted.

The effect of using the drug at a dose of 0.25 mg (8 million IU) every other day on the metabolism of medicinal products in patients with multiple sclerosis is unknown.

When using Extavia, glucocorticosteroids and adrenocorticotropic hormone (ACTH), prescribed for up to 28 days for the treatment of exacerbations, are well tolerated. The use of Extavia simultaneously with other immunomodulators, besides glucocorticosteroids or ACTH, has not been studied.

Interferons reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when prescribing Extavia in combination with medicinal products with a narrow therapeutic index, the clearance of which largely depends on the hepatic cytochrome P450 system (e.g., anticonvulsants, antidepressants).

Caution should also be exercised with the concomitant use of any drugs affecting the hematopoietic system.

Due to the lack of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F). Do not freeze. Store the reconstituted solution for 3 hours at a temperature from 2°C (35.6°F) to 8°C (46.4°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.