Infibet® (Infibeta®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceInterferon beta-1bInterferon beta-1b
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  • Betaferon®
    lyophilizate PC 
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    solution PC 
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  • Infibet®
    lyophilizate PC 
    GENERIUM, CJSC     Russia
  • Extavia
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    Novartis Pharma AG     Switzerland
    • Dosage form: & nbspLyophilizate for the preparation of a solution for subcutaneous administration.
    Composition:

    1 bottle with the drug contains: active substance: interferon beta-lb - 0.3 mg (corresponding to 9.6 million ME); Excipients: human albumin - 15 mg, mannitol - 15 mg.

    1 bottle with a solvent contains: sodium chloride solution 0.54% for injection.

    1 ml of the solvent contains: sodium chloride - 5.4 mg, water for injection - up to 1 ml.

    Description:
    Amorphous mass from white to slightly yellowish color.

    Pharmacotherapeutic group:Cytokine.
    ATX: & nbsp

    L.03.A.08   Interferon beta-1b

    Pharmacodynamics:Interferon beta-lb has antiviral and immunomodulating activity. The mechanism of action of interferon beta-lb for multiple sclerosis (PC) is not definitively established. However, it is known that the biological effect of interferon beta-lb is mediated by its interaction with specific receptors that are found on the surface of human cells. The binding of interferon-beta-lb to these receptors induces the expression of a number of substances that are considered as mediators of the biological effects of interferon beta-lb.The content of some of these substances was determined in serum and fractions of blood cells of patients receiving interferon beta-lb. Interferon beta-lb decreases the binding ability of the interferon y receptor and increases its internalization and degradation. In addition, interferon beta-lb increases the suppressor activity of peripheral blood mononuclear cells.
    In both remitting and secondary-progressive multiple sclerosis, interferon beta-lb treatment reduces the incidence (by 30%) and severity of clinical exacerbations of the disease, the number of hospitalizations and the need for treatment with glucocorticosteroids, and also prolongs the duration of remission.
    In patients with a second-progressive PC, interferon beta-lb treatment can delay further progression of the disease and the onset of disability, including severe disability (ie, when patients are forced to use the wheelchair) for up to 12 months. This effect is observed in patients with both exacerbations of the disease and without exacerbations, as well as with any index of disability (in the study, patients rated from 3 to 6.5 points on the extended scale of assessment of the state of disability) participated.
    The results of magnetic resonance imaging of the brain of patients with remitting and secondary-progressive multiple sclerosis on the background of interferon beta-lb treatment confirm 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 foci.
    Pharmacokinetics:
    After subcutaneous administration of interferon beta-lb at a recommended dose of 0.25 mg, serum interferon beta-lb concentrations are low or not at all. In this regard, there is no information on the pharmacokinetics of interferon beta-lb in patients with multiple sclerosis receiving the drug at the recommended dose.
    After subcutaneous injection. 0.5 mg of the drug the maximum concentration of interferon beta-lb in plasma is reached 1-8 hours after injection and is about 40 IU / ml. Absolute bioavailability of interferon beta-lb with subcutaneous administration is about 50%. With intravenous administration of the drug, the clearance and half-life of interferon beta-lb from serum averaged 30 ml / min / kg and 5 h respectively. Administration of the drug every other day does not lead to an increase in the concentration of interferon beta-lb in the blood plasma, and its pharmacokinetics does not change during the course of therapy.
    When subcutaneous injection of the drug at a dose of 0.25 mg every other day, the content of biological response markers (neopterin, β2-microglobulin and immunosuppressive cytokine, interleukin-10) is significantly increased compared to baseline values ​​6-12 hours after the first dose of the drug. The concentration of these substances reached a maximum in 40-124 hours and remained elevated during the 7-day (168 h) study period.
    Indications:
    Clinically isolated syndrome (CIC) (the only clinical episode of demyelination that suggests multiple sclerosis, with the exclusion of alternative diagnoses) with sufficient inflammation for the appointment of intravenous corticosteroids.
    Remitting multiple sclerosis (RRMS) - to reduce the frequency and severity of exacerbations in ambulatory patients (i.e. patients who can walk unaided) with a history of not less than 2 exacerbations during the last 2 years, followed by complete or incomplete recovery of neurologic deficiency.
    Secondary-progressive multiple sclerosis with an active course of the disease,characterized by exacerbations or marked worsening of neurological functions during the last two years - to reduce the frequency and severity of clinical exacerbations of the disease, as well as to slow the progression of the disease.
    Contraindications:Hypersensitivity to the components of the drug, pregnancy, the period of breastfeeding, children under 18 years. Severe depression and (or) suicidal thoughts. Decompensated hepatic insufficiency.
    Carefully:Heart disease, in particular, cardiac insufficiency III-IV functional class according to the classification of the New York Heart Association (NYHA), cardiomyopathy; convulsions in the anamnesis; monoclonal gammopathy; anemia, thrombocytopenia, leukopenia; abnormal liver function.
    Pregnancy and lactation:
    Pregnancy

    It is not known whether interferon beta-lb is able to cause abnormalities in the fetus in the treatment of pregnant women or affect human reproductive function. In controlled clinical trials in patients with multiple sclerosis have been cases of spontaneous abortion.In studies in rhesus monkeys, human interferon beta-lb exerted an embryotoxic effect and in higher doses caused an increase in the incidence of spontaneous abortions. Women of reproductive age should be treated with safe methods of contraception. If pregnancy occurs during treatment with Infibet® or when planning pregnancy, a woman should be informed of the potential risk; it is recommended to cancel the drug.

    Breastfeeding period

    It is not known whether interferon beta-lb is excreted in breast milk. Given the theoretical possibility of developing unwanted reactions to interferon beta-lb in infants who are breastfeeding, it is necessary to stop breastfeeding or to cancel the drug.
    Dosing and Administration:Treatment with Infibet® should be started under the supervision of a physician with experience in the management of multiple sclerosis. At present, the question of the duration of therapy with Infibet® remains unresolved. The duration of treatment is determined by the doctor. Preparation of the injection solution To dissolve the lyophilizate, use the applied solvent in the vial (sodium chloride solution 0.54%), syringe and needle.1.2 ml of solvent are introduced into the vial with Infibet®. The powder must be dissolved completely without shaking. Before use, inspect the prepared solution. In the presence of particles or a change in the color of the solution, it can not be used. 1 ml of cooked The solution contains 0.25 mg (8 ppm) ME) interferon beta-lb.

    The rules for the preparation of injection solution and the administration of subcutaneous injections are described in the section with the same name.

    Mode of application

    Subcutaneously.

    Dosing regimen

    The recommended dose of Infibet ® 0.25 mg (8 million. ME), which is contained in 1 ml of the prepared solution, is administered subcutaneously every other day. At the beginning of treatment, it is recommended that the dose is titrated as follows.

    The initial dose is 62.5 mg (0.25 ml) subcutaneously every second day and gradually increased up to 250 micrograms (1.0 ml) and every other day. The duration of the titration period is set individually, depending on the tolerability of the drug. When a single clinical episode of demyelination, suggesting multiple sclerosis, recommended titration scheme shown in the table.

    Day of treatment

    Dose, μg

    Volume of drug solution, ml

    1,3,5

    62,5

    0,25

    7, 9,11

    125

    0,5

    13, 15, 17

    187,5

    0,75

    >19

    250

    1,0

    In patients with relapsing-remitting sclerosis, who have had less than two exacerbations in the past 2 years or in patients with secondary-progressive multiple sclerosis who have been in the inactive phase during the past 2 years, the use of the drug is not recommended.

    Patients who are not experiencing any improvement (eg, persistent progression of the disease on a scale EDSS within 6 months or the need for 3 or more courses of corticotropin therapy or glucocorticosteroids), treatment with Infibet® should be discontinued.

    Rules for the preparation of injection solution and subcutaneous injection.

    To prepare a solution for subcutaneous injection, mix the contents of the vials with the preparation and the solvent. For this it is necessary to prepare:

    1 bottle with drug

    1 bottle with solvent *

    1 syringe with a capacity of 2 ml

    1 syringe with capacity 1ml **

    2 long needles

    1 short needle

    2 napkins alcohol.

    Do not use a vial with glass or closure defects.

    Attention:

    * The bottle with the solvent should be removed from the refrigerator for 10-15 minutes.before injection. ** If you plan to use an auto injector, take a 1 ml syringe for the injection solution.

    - Wash your hands with warm water and soap.

    - Remove the plastic covers from the vials.

    - Rub rubber stoppers with an alcohol sponge.

    - Remove the 2 ml syringe from the blister pack.

    - Put a long needle on the syringe and remove the protective cap from it.

    - Pierce the rubber plug of the vial with the solvent with a long needle and take 1.2 ml of the solution from the vial.

    - Remove the filled syringe with the needle from the vial, remove the air bubbles from the syringe, change the needle to the second long one.

    - Puncture the rubber stopper of the vial with the drug, directing the needle to the side wall of the vial. Slowly inject the solvent (1.2 ml) over the wall of the vial, avoiding foaming.

    - Gently shaking the vial, dissolve its contents, without removing the syringe from the vial. Do not shake! The finished solution must be transparent, free of visible particles.

    - Turn the vial over and put the prepared solution into the syringe, make sure that the tip of the needle is immersed in the solution. At the beginning of the treatment, the volume of the solution indicated in the titration table of doses is drawn into the syringe.

    - In case of using an autoinjector, take a solution with a 1 ml syringe.

    - Remove the syringe from the vial, release air and excess drug from the syringe to the mark 1.0 ml, holding the syringe upright, with the needle up.

    - Replace the long needle with a short one for subcutaneous injection.

    Recommendations for choosing a hypodermic injection site

    The drug is injected with a syringe with a short needle subcutaneously into soft tissues, located far from the joints and nerves. Places for injection should be located in the following parts of the body:

    - Hands (back of the shoulder).

    - Belly (excluding the navel and waist area).

    - Buttocks.

    Hips (anterior and outer lateral surface, excluding the groin and knee area). Place the injection sites alternating, choosing each time a new one, according to the diagram in Figure 1. For convenience, write down where and when the injections were made or make the appropriate notes in the table in Figure 1.

    Attention! Do not inject into areas where there are bumps, swelling, hard knots, or pain. Do not inject into areas of the skin that have changed color, or if there are crusts, depressions or damage. If you find yourself experiencing similar changes, consult your doctor.

    Rules for subcutaneous injection without an autoinjector:

    - Wipe the skin at the injection site with a sponge napkin and wait until the skin has dried.

    - Take a 2 ml filled syringe with a short needle and remove the protective cap from the needle.

    - Collect the skin in a crease.

    - With a firm movement, insert the needle into the raised area of ​​the skin at an angle of 90 ° for the entire length.

    - Slowly insert all the solution contained in the syringe (not more than 1.0 ml), evenly pressing on the piston, and remove the needle from the skin.

    - Press the alcoholic napkin to the injection site and gently massage the skin.

    - Remove used syringes, needles, vials and napkins in the waste container.

    The rules for subcutaneous injection with an autoinjector:

    - Wipe the skin at the injection site with a sponge napkin and wait until the skin has dried.

    - Take a 1 ml filled syringe with a short needle and remove the protective cap from the needle.

    - Fill the filled syringe in the auto injector and make yourself a subcutaneous injection, guided by the rules described in the instructions to the autoinjector.

    A solution for subcutaneous injection is prepared immediately before use.

    Side effects:

    The following are undesirable events observed with a frequency of 2% and higher than in the placebo group (inactive drug) in patients who received interferon beta-lb in a dose of 0.25 mg or 0.16 mg / m2 a day lasting up to three years. Flu-like symptoms can be weakened by using non-steroidal anti-inflammatory drugs.

    Experience with the use of interferon beta-lb for the treatment of patients with multiple sclerosis is sufficiently limited, therefore, negative reactions that occur at a low frequency may not yet be observed. To describe a specific reaction, its synonyms and associated states, the most appropriate term is used from the Medical Dictionary for regulatory activity (MedDRA).

    General reactions

    Reaction at the injection site, asthenia, weakness of the complex, flu-like symptoms, headache, fever, chills, peripheral edema, chest pain, pain of different localization, general malaise, necrosis at the injection site.

    The cardiovascular system

    Increase in blood pressure.

    Digestive system Abdominal pain.

    Blood and lymphatic system

    Lymphocytopenia <1500 / mm3, neutropenia <1500 / mm3, leukopenia <3000 / mm3; lymphadenopathy.

    Metabolic and alimentary disorders

    Increase in activity of enzymes in the blood: aspartate aminotransferase (ACT) 5 times from the initial value, alanine aminotransferase (ALT) 5 times from the initial value.

    Musculoskeletal system

    Myasthenia gravis, myalgia, leg cramps.

    Nervous system

    Insomnia, impaired coordination.

    Respiratory system

    Dyspnea.

    Leather

    Rashes, skin lesions.

    Genitourinary system

    Imperative urge to urinate, in women - metrorrhagia

    (acyclic uterine bleeding), in men - impotence.

    The list of side effects presented below is based on observation of

    application of the drug after market entry.

    The frequency of side effects is classified as follows:

    Often (>10%), often (<10% - >1%), infrequently (<1% - >0.1%), rarely (<0,1 % - >0.01%) and very rarely (<0.01%).

    General reactions

    Very often: flu-like symptoms (fever, chills, myalgia, headache or excessive sweating) *. The frequency of these symptoms decreases with time.

    Rarely: general malaise, chest pain, weight loss, weight gain.

    Local Reactions

    Very often: reactions at the injection site (hyperemia, local edema) *, inflammation *, pain *.

    Often: necrosis at the injection site *.

    Over time, with the continuation of treatment, the frequency of reactions at the site of administration of the drug is usually reduced.

    Blood and lymphatic system

    Infrequent: anemia, thrombocytopenia, leukopenia.

    Rarely: lymphadenopathy.

    Endocrine disorders

    Rarely: thyroid dysfunction, including hyperthyroidism, hypothyroidism.

    Metabolic disorders

    Rarely: increased concentration of triglycerides.

    Nervous system

    Infrequently: muscle hypertonia, depression.

    Rarely: convulsions, confusion, agitation, emotional lability, suicidal attempts, anorexia, dizziness.

    The cardiovascular system

    Infrequent: increased blood pressure.

    Rarely: cardiomyopathy, tachycardia, severe palpitations.

    Very rarely: vasodilation.

    Respiratory system

    Rarely: dyspnea, bronchospasm.

    Gastrointestinal tract

    Infrequent: nausea and vomiting.

    Rarely: pancreatitis, diarrhea.

    Liver and bile ducts

    Infrequently: increased activity ACT, ALT in the blood.

    Rarely: increased activity of γ-glutamyltransferase, bilirubin concentration in the blood, hepatitis.

    Skin and subcutaneous tissue

    Infrequently: alopecia, hives, itching of the skin, skin rashes.

    Rarely: discoloration of the skin.

    Skeletal musculature

    Infrequently: myalgia.

    Rarely: arthralgia.

    Female Reproductive System

    Rarely: menstrual cycle disorders.

    Very rarely: menorrhagia (prolonged menstrual bleeding).

    Allergic reactions

    Rarely: anaphylactic reactions.

    * frequency is indicated on the basis of clinical trial data.

    Overdose:
    When Infibet® was injected intravenously at a dose of up to 5500 micrograms (176 million ME), serious adverse events were not revealed to adults with oncological diseases three times a week.
    Against the background of the use of interferon beta-lb, glucocorticosteroids and corticotropin, prescribed for up to 28 days in the treatment of exacerbations, are well tolerated.
    Interaction:
    The use of interferon beta-lb concomitantly with other immunomodulators, in addition to glucocorticosteroids or corticotropin, has not been studied.

    Care should be taken when using interferon beta-lb in combination with other drugs metabolized by certain isoenzymes of cytochrome P450. This group includes some widely antipyretic and analgesic agents, antidepressants, anticonvulsants. It is also necessary to be careful when using any drugs that affect the hematopoiesis system at the same time.

    If you need to take any other medications for a long period of time, you should consult your doctor.

    Due to the lack of compatibility studies, this medication should not be mixed with other medications.
    Special instructions:

    Immune disorders

    The use of cytokines in patients with monoclonal gammapathy was sometimes accompanied by a systemic increase in capillary permeability with the development of shock and death.

    Gastrointestinal disorders

    In rare cases, against the background of the use of Infibet®, there was a development of pancreatitis, in most cases associated with the presence of hypertriglyceridemia.

    The defeat of the nervous system

    Patients should be informed that the side effect of Infibet® can be depression and suicidal thoughts, which should immediately be consulted by a doctor. In two controlled clinical trials involving. 1657 patients with a secondary progressive PC there were no significant differences in the incidence of depression and suicidal thoughts when using interferon beta-lb, or placebo.Nevertheless, caution should be exercised when prescribing Infibet® to patients with depressive disorders and suicidal thoughts in the anamnesis. If such phenomena occur on the background of treatment, consider whether it is advisable to discontinue Infibet®.

    The drug Infibet® should be used with caution in patients with a history of seizures.

    This drug contains human albumin, and for this reason there is very little risk of transmission of viral diseases.

    The theoretical risk of transmission of Creutzfeldt-Jakob disease is also considered highly unlikely.

    Changes in laboratory indicators

    In addition to the standard laboratory tests administered in patients with multiple sclerosis, before starting therapy with Infibet® and regularly during the treatment, it is recommended to conduct a detailed blood test, including the determination of the leukocyte formula, platelet counts and biochemical blood test, and also check the liver function (e.g., activity of aspartate aminotransferase (ACT), alanine aminotransferase (AJIT) and γ-glutamyltransferase (γ-HT)).When managing patients with anemia, thrombocytopenia, or leukopenia (individually or in combination), a more detailed monitoring of the expanded blood test may be required, including the determination of the number of red blood cells, leukocytes, platelets and the leukocyte formula.

    Disturbances from the liver and bile ducts

    Clinical studies have shown that interferon therapy with beta-lb often can lead to an asymptomatic increase in the activity of "hepatic" transaminases, which in most cases is expressed only slightly and is transient.

    As with other beta interferons, severe liver damage (including liver failure) with Infibet® is rarely observed. The most severe cases were observed in patients exposed to hepatotoxic drugs or substances, as well as in certain concomitant diseases (eg malignant tumors with metastasis, severe infections and sepsis, alcoholism).

    When treating Infibet®, it is necessary to monitor liver function (including clinical evaluation).Increased activity of transaminases in the serum requires careful monitoring and examination. With a significant increase in the activity of transaminases in the blood serum or the appearance of signs of liver damage (eg, jaundice), the drug should be discontinued. In the absence of clinical signs of liver damage or after the normalization of the activity of "liver" enzymes, it is possible to resume therapy with Infibet® with monitoring the liver function.

    Violation of the kidneys and urinary tract

    Care should be taken when administering the drug to patients with severe renal failure.

    Endocrine disorders

    Patients with thyroid dysfunction are recommended to check the function of the thyroid gland (thyroid hormones, thyroid-stimulating hormone) regularly, and in other cases - according to clinical indications.

    Diseases of the cardiovascular system

    The drug Infibet® should be used with caution in patients with heart disease, in particular, with heart failure III-IV functional class according to the classification of the New York Heart Association (NYHA).

    If against the background of Infibet® treatment, cardiomyopathy develops and it is supposed that this is due to the use of the drug, treatment with Infibet® should be stopped.

    General violations and violations at the injection site

    Serious allergic reactions can occur (rare, but manifested in acute and severe form, such as bronchospasm, anaphylaxis and urticaria).

    If signs of damage to the integrity of the skin appear (for example, the flow of fluid from the injection site), the patient should consult a doctor before continuing injecting Infibet®.

    Patients receiving Infibet® received necrosis at the injection site (see "Side Effects" section).

    Necrosis can be extensive and spread to the muscular fascia, as well as adipose tissue and, as a result, lead to the formation of scars. In some cases, it is necessary to remove the necrotic areas or, more rarely, skin transplantation. The healing process can take up to 6 months. When multiple foci of necrosis occur, treatment with Infibet® should be stopped until the wound is completely healed.In the presence of a single focus, if necrosis is not too extensive, the use of Infibet® can be continued, as in some patients the healing of the necrotic site at the injection site occurred against the background of the Infibet® drug.

    To reduce the risk of developing a reaction and necrosis at the injection site, patients should be recommended:

    - to carry out injections, strictly observing the rules of asepsis;

    - each time to change the injection site;

    - administer the drug strictly subcutaneously.

    Periodically, one should monitor the correctness of performing independent injections, especially when local reactions appear.

    Immunogenicity

    As in the treatment of any other drug, containing proteins, with Use of the Infibet® product antibodies. In a number of controlled clinical trials, serum analysis was performed every 3 months to detect the formation of antibodies to interferon beta-lb. In these studies, it was shown that neutralizing antibodies to interferon beta-lb developed in 23-41% of patients, which was confirmed by at least two subsequent positive results of laboratory tests.In 43-55% of these patients, in subsequent laboratory studies, a stable absence of antibodies to interferon beta-lb. In a study involving patients with a clinically isolated syndrome that suggests multiple sclerosis, neutralizing activity, which was measured every 6 months, during appropriate visits, 16.5-25.2% of interferon-lb patients. Neutralizing activity was detected at least once in 30% (75) of those receiving interferon beta-lb patients; in 23% (17) of them before the study was completed, the status of antibodies again became negative.

    During the two-year study period, the development of neutralizing activity was not associated with a decrease in clinical efficacy (in terms of time to the onset of clinically significant multiple sclerosis).

    It has not been proven that the presence of neutralizing antibodies has any significant effect on clinical outcomes. With the development of neutralizing activity, the appearance of any side reactions was not associated. The decision to continue or discontinue therapy should be based on the indicators of the clinical activity of the disease, and not on the status neutralizing activity.

    Use in children

    A systematic study of the efficacy and safety of Infibet® in children and adolescents under the age of 18 was not carried out.

    Effect on the ability to drive transp. cf. and fur:Special studies have not been conducted. Undesirable effects from the CNS can affect the ability to drive and work with machinery. In this regard, care must be taken when practicing; potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
    Form release / dosage:
    Lyophilizate for the preparation of a solution for subcutaneous injection 9.6 million ME.
    Packaging:
    Lyophilizate for the preparation of a solution for subcutaneous administration of 9.6 million ME in glass bottles, sealed with rubber stoppers, with aluminum-plastic caps with control of the first opening.
    For 1.2 ml of solvent in glass bottles, sealed with rubber stoppers, with aluminum-plastic caps with control of the first opening. 5 vials of the preparation and the solvent in the contour cell packaging from the film of polyvinyl chloride or polyethylene terephthalate.
    For 1 or 3 contour packs with a preparation and a solvent complete with 5 or 15 syringes with a capacity of 2 ml without needles, 5 or 15 syringes with a capacity of 1 ml without needles, 10 or 30 needles long (for solution), 5 or 15 needles short (for subcutaneous administration), 10 or 30 napkins with alcohol and instructions for use in a pack of cardboard.
    Each syringe and needle is placed in a sterile disposable polyvinyl chloride film and paper laminated. Napkin alcohol packed in a multi-layer material, consisting of aluminum foil and polyethylene film. At the junction of the lid and the front edge of the pack, a self-adhesive label is affixed to control the first opening.
    Storage conditions:At a temperature of 2 to 8 ° C. Immediately before the use of the drug it is allowed to store it in its original packaging at a temperature not exceeding 15 ° C - no more than 15 days, at a temperature of no higher than 25 ° C - no more than 7 days. Do not freeze. Keep out of the reach of children.
    Shelf life:Preparation - 2 years, solvent - 3 years. Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-000869
    Date of registration:18.10.2011
    Date of cancellation:2016-10-18
    The owner of the registration certificate:GENERIUM, CJSC GENERIUM, CJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp12.12.2015
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