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medicalmeds.eu Medicines Cytokine. Means for treatment of multiple sclerosis. Interferon beta 1b

Interferon beta 1b

Препарат Интерферон бета-1b. ЗАО "Биокад" Россия


Producer: JSC Biocad Russia

Code of automatic telephone exchange: L03AB08

Release form: Liquid dosage forms. Solution for hypodermic introduction.

Indications to use: Multiple sclerosis.


General characteristics. Structure:

Active ingredient: 8 million ME of interferon beta 1b human recombinant.

Excipients: acetate sodium trihydrate, acetic acid ice, a dextran of 50-70 thousand, polysorbate 80, Mannitolum, dinatrium of an edetat a dihydrate, water for injections.




Pharmacological properties:

Pharmacodynamics. Recombinant interferon beta 1b is emitted from cells of Escherichia coli in which genome the gene of human interferon a beta coding amino acid серинв the 17th position is implemented. Interferon beta 1b represents neglikozilirovanny protein of molecular weight 18500 дальтон, consisting of 165 amino acids.

Interferona on the structure are proteins and belong to family of cytokines. The molecular mass of interferon is in range from 15000 to 21000 дальтон. Allocate three main classes of interferon: alpha, beta and scale. Interferona the alpha, a beta and scale have the similar mechanism of action, however various biological effects. Activity of interferon is species-specific, and, therefore, it is possible to study their effects only on cultures of cells of the person or in vivo on the person.

Interferon beta 1b has antiviral and immunomodulatory activities. The mechanism of effect of interferon beta 1b at multiple sclerosis is up to the end not installed. However it is known that the biological effect of interferon beta 1b is mediated by its interaction with specific receptors which are found on a surface of cells of the person. Binding of interferon beta 1b with these receptors induces an expression of a number of substances which are considered as mediators of biological effects of interferon beta 1b. Keeping of some of these substances was defined in serum and fractions of the sick cells receiving interferon beta 1b. Interferon beta 1b scale reduces the connecting ability of a receptor of interferon and increases its internalization and degradation. Besides, interferon beta 1b increases suppressor activity of mononuclear cells of peripheral blood.

Purposeful researches for the purpose of definition of influence of interferon beta 1b on function of cardiovascular system, respiratory and endocrine systems were not conducted.

Results of clinical trials. Remittiruyushchy multiple sclerosis. Within controlled clinical trial of patients with a remittiruyushchy form of multiple sclerosis, capable to independent walking (EDSS from 0 to 5.5), receiving drug of interferon beta 1b, obtained data, that drug reduces the frequency of aggravations by 30%, reduces weight of aggravations and number of hospitalization because of a basic disease. Further increase in an interval between aggravations and a tendency to delay of progressing of remittiruyushchy multiple sclerosis were shown.

The secondary progressing multiple sclerosis. Two controlled clinical trials which included 1657 patients with for the second time the progressing form of multiple sclerosis were conducted. Patients with a reference value of EDSS from 3 to 6.5 points participated in researches, i.e. patients were capable to go independently. At assessment of the main final point of the research "time to the confirmed progression", i.e. ability to slow down progressing of a disease in researches, contradictory data were obtained.

One or the other researches showed statistically significant delay of speed of progressing of an invalidism (the relation of risks = 0.69 at 95% a confidence interval (0.55, 0.86), р =0.0010, decrease in risks made 31% in group of therapy by run-1b interferon) and increase in time until loss of an opportunity to move independently, i.e. uses of a wheelchair or EDSS 7.0 (the relation of risks = 0.61 at 95% a confidence interval (0.44, 0.85), р =0.0036, decrease in risks made 39% in group of therapy by interferon beta 1b) among the patients accepting interferon beta 1b. The therapeutic effect of drug remained also in the subsequent period of observation regardless of the frequency of aggravations.

In the second research of drug of interferon beta 1b at patients with for the second time the progressing form of multiple sclerosis did not show delay of speed of progressing. However, the patients included in this research had smaller activity of a disease, than patients in other researches at the vtorichnoprogressiruyushchy course of multiple sclerosis. When carrying out retrospective meta-analysis of these both researches statistically significant effect (р =0.0076 is shown, when comparing groups of the patients receiving interferon of beta 1b 8 million ME and groups of placebo).

The retrospective analysis on subgroups showed that influence of news agency the speed of progressing is more expressed in group of patients with high activity of a disease prior to therapy (the relation of risks = 0.72 at 95% a confidence interval (0.59, 0.88), р =0.0011, decrease in risks made 28% in group of patients with aggravations or a bystry progression of EDSS receiving interferon beta 1b in comparison with group of placebo). By results of the carried-out analysis it is possible to conclude that the analysis of frequency of a recurrence and bystry progression EDSS (EDSS> of 1 point or> 0.5 at basic EDSS≥6 of points in 2 years preceding therapy) can promote identification of patients with the active course of a disease. In these researches decrease in frequency of aggravations (30%) was also shown. It was not shown that interferon beta 1b exerts impact on duration of aggravations.

The clinical isolated syndrome. One controlled clinical trial of interferon beta 1b was conducted at patients with the clinically isolated syndrome (CIS). PUSSYCATS are assumed by existence of the only clinical episode of demyelination and/or, at least, two clinically not proving centers on the T2-weighed images of MRT which are not enough for diagnosis of clinically reliable PC. It is established what leads further PUSSYCATS with a high probability to development of multiple sclerosis.

The research joined patients with one clinical center or two and more centers on MRT provided that all alternative diseases which could serve as the most probable cause of the available symptoms except multiple sclerosis, were excluded.

This research consisted of 2 phases, placebo - a controlled phase and a phase of the subsequent observation. The placebo-controlled phase had duration of 2 years or until transition of the patient to the clinically reliable multiple sclerosis (CRMS). After placebo end - a controlled phase the patient was transferred to a phase of the subsequent observation against the background of therapy by interferon beta 1b. For the purpose of assessment of the early and delayed effect of purpose of interferon beta 1b groups of patients, originally randomized on interferon beta 1b (group of immediate treatment) and placebo (group of the delayed treatment) were compared. During the research patients and researchers remained zasleplena concerning distribution of patients in groups of therapy.

Table 1. Efficiency of interferon beta 1b within clinical trials of BENEFIT and the prolonged observation of patients of the research BENEFIT.

  Results of the 2nd summer therapy Placebo-controlled phase Results of the 3rd year of therapy
Subsequent phase of open therapy
Results following the results of the 5th year of observation
Subsequent phase
open therapy
 
  Interferon beta 1b
8 million ME
n=292
Placebo
n=176
Group
immediate
treatments by interferon beta 1b
8 million ME
n=292
Group of the delayed treatment by interferon beta 1b
8 million ME
n=176
Group of immediate treatment by interferon beta 1b
8 million ME
n=292
Group of the delayed treatment by interferon beta 1b
8 million ME
n=176
 
 
Number
patients
completed
this phase
271 (93%) 166 (94%) 249 (85%) 143 (81%) 235 (80%) 123 (70%)  
 
Main indicators of efficiency
Time before development of the clinically reliable multiple sclerosis (CRMS)
According to Kaplan-Maier 28% 45% 37% 51% 46% 57%
Reduction
risk
47% in comparison with placebo 41% in comparison with group of the delayed treatment by interferon beta 1b 37% in comparison with group of the delayed treatment by interferon beta 1b
The relation of risks at 95% of DI HR=0.53 (0.39, 0.73) HR=0.59 (0.42, 0.83) HR=0.63 (0.48, 0.83)
Lograngovy test p <0.0001
interferon beta 1b prolonged time before KDRS for 363 days, of 255 days in group of placebo (up to 618 days in group of interferon beta 1b)
É = É =
Time before transformation in PC by criteria Mac-Donald
According to Kaplan-Maier 69% 85% Was not the main final point Was not the main final point
Reduction
risk
43% in comparison with group of placebo
The relation of risks at 95% of DI HR=0.57 (0.46, 0.71)
Lograngovy test p <0.0001
Time to EDSS progression
According to Kaplan-Maier Was not main
final point
16% 24% 25% 29%
Reduction
risk
  40% in comparison with group of the delayed treatment by interferon beta 1b 24% in comparison with group of the delayed treatment by interferon beta 1b  
The relation of risks at 95% of DI HR=0.60 (0.39, 0.92) HR=0.76 (0.52, 1.11)  
Lograngovy test É = É =  

In placebo - a controlled phase of a research interferon beta 1b statistically authentically prevented transition of PUSSYCATS to KDRS. In group of the patients receiving interferon beta 1b the transformation delay in reliable multiple sclerosis by criteria Mac-Donald is shown (see table 1).

The analysis of subgroups depending on initial factors showed efficiency of interferon beta 1b concerning prevention of transformation in KDRS in all subgroups. The risk of transformation in KDRS within 2 years was higher in group of patients with monofocal TURNED SOUR with 9 and more centers on the T2-weighed images or with existence of the centers accumulating contrast according to MRT at the beginning of the research. Efficiency of interferon beta 1b in group of patients with multifocal clinical manifestations did not depend on initial indicators of MRT that demonstrates high risk of transformation of PUSSYCATS in KDRS at patients of this group.

There is no standard determination of high risk now, however it is possible to carry patients with monofocal to group of high risk of development of KDRS TURNED SOUR (clinical manifestation of 1 center in TsNS) and at least 9 centers on MRT in T2 mode and/or accumulating a contrast agent. Patients with multifocal TURNED SOUR (clinical manifestations> 1 center in TsNS) treat group of high risk of development of KDRS irrespective of quantity of the centers on MRT. Anyway, the decision on purpose of interferon beta 1b has to be made, proceeding from the conclusion about high risk of development of KDRS in the patient.

Therapy with interferon beta 1b was well transferred by patients what points low interest of the left patients to (93% completed a research).

For improvement of portability titration of a dose of interferon beta 1b was carried out, NPVP at the beginning of therapy were applied. Besides, the autoinjector at most of patients throughout all research was applied.

Further interferon beta 1b kept high performance on ability to prevent development of KDRS after 3 and 5 years of observation (tab. 1) in spite of the fact that most of the patients receiving placebo began therapy with interferon beta 1b in 2 years after the beginning of a research. The confirmed EDSS progression (increase in EDSS, at least, on one visit in comparison with a reference value) was lower in group of immediate treatment (tab. 1, the considerable effect is revealed on the 3rd year of therapy, but on the 5th the effect is absent). Most of patients in both groups had no progressing of disability for the 5-year period. The convincing evidence in favor of influence on this result of immediate purpose of interferon beta 1b is not obtained. Influence of immediate treatment by interferon beta-1 is not shown to b on quality of life of patients.

The Remittiruyushchy, secondary progressing multiple sclerosis and the clinical isolated syndrome. Efficiency of interferon beta 1b is shown in all clinical trials on ability to reduce the activity of a disease (an acute inflammation in TsNS and permanent damage of fabric) estimated on MRT indicators. The ratio of clinical activity of multiple sclerosis and activity of a disease on MRT-indicators is up to the end not established now.

Pharmacokinetics. After п / to administration of interferon beta 1b in the recommended dose of 8 million ME its serumal concentration low or are not defined at all. In this regard, data on drug pharmacokinetics at the patients with multiple sclerosis receiving interferon beta 1b in the recommended dose no. After п / to introduction of 16 million ME interferon beta 1b the maximum levels in plasma make about 40 ME/ml in 1-8 h after an injection.

By results of numerous clinical trials clearance of interferon beta 1b and drug T1/2 from serum averages 30 ml/min. and 5 h respectively. Absolute bioavailability of interferon beta 1b at п / to introduction equals about 50%.

Administration of interferon beta 1b every other day does not lead to increase in level of drug in a blood plasma, and its pharmacokinetics during a therapy course, apparently, does not change.

At п / to use of interferon beta 1b in a dose of 0.25 mg every other day levels of markers of the biological answer (neopterine, beta2-microglobulin and immunosuppressive cytokine interleykin-10) considerably increased in comparison with initial indicators in 6-12 h after introduction of the first dose of drug. They reached peak in 40-124 h and remained raised throughout 7-day (168 h) the research period. Communication between levels in plasma of interferon beta 1b or levels of the markers induced by it and the mechanism of effect of interferon beta 1b at multiple sclerosis is not established.


Indications to use:

— the clinically isolated syndrome (CIS) (the only clinical episode of demyelination allowing to assume multiple sclerosis on condition of an exception of alternative diagnoses) with sufficient expressiveness of inflammatory process for purpose of intravenous corticosteroids - for delay of transition to KDRS at patients with high risk of development of KDRS.

There is no standard determination of high risk. According to a research patients with monofocal treat group of high risk of development of KDRS TURNED SOUR (clinical manifestations of 1 center in TsNS) and the T2-centers on MRT and/or accumulating a contrast agent the centers. Patients with multifocal TURNED SOUR (clinical manifestations> 1 center in TsNS) treat group of high risk of development of KDRS irrespective of quantity of the centers on MRT;

— remittiruyushchy multiple sclerosis - for reduction of frequency and weight of exacerbations of multiple sclerosis at patients capable to go without assistance, in the presence in the anamnesis not less than 2 exacerbations of a disease for the last 2 years with the subsequent complete or incomplete recovery of neurologic deficit;

— the secondary progressing multiple sclerosis with the active course of a disease which is characterized by aggravations or the expressed deterioration in neurologic functions within the last 2 years - for reduction of frequency and weight of clinical exacerbations of a disease, and also for delay of rates to progress diseases.

To apply strictly on doctor's orders.


Route of administration and doses:

Treatment by drug of interferon beta 1b should be begun under observation of the doctor having experience of treatment scattered a sclerosis.

Adults. The recommended dose of interferon of beta 1b 8 million ME is entered п / to every other day.

Children. Formal clinical and pharmacokinetic trials in children's and teenage population were not conducted. The limited published data confirms a comparable profile of safety of drug of interferon beta 1b in a dose of 8 million ME п / to every other day in group of patients from 12 to 16 years, in comparison with adult population. There is no information on use of drug of interferon beta 1b at persons 12 years are younger, drug cannot be used in the specified group of patients.

In an initiation of treatment it is usually recommended to carry out titration of a dose. Treatment it is necessary to begin with introduction 2 million ME п / to every other day, gradually increasing the dose to 8 million ME entered also every other day. The period of titration of a dose can vary depending on individual portability of drug.

Table 2. Scheme of titration of a dose *

 

Day of treatment Dose, one million ME The volume of drug, ml depending on the applied release form
8 million ME/0.5 of ml 8 million ME/0.5 of ml
1, 3, 5 2 0.125 0.25
7, 9, 11 4 0.25 0.5
13, 15, 17 6 0.375 0.75
≥19 8 0.5 1.0

* The period of titration can be increased at development of undesirable reactions

Treatment duration is not established now. There are results of clinical trials in which treatment duration at patients with the remittiruyushchy and secondary progressing multiple sclerosis achieved 5 and 3 years respectively. In group of patients with the recurrent course of multiple sclerosis high performance is shown within the first 2 years. Further three years' observation showed preservation of indicators of efficiency during the entire period of treatment. At patients with clinically isolated syndrome the considerable delay of transformation in reliable multiple sclerosis on an extent of more than 5 years was observed.

Therapy by interferon beta 1b is not shown to patients with recurrent remittiruyushchey a form of multiple sclerosis which for last 2 years had less than 2 aggravations, or to patients to the secondary progressing multiple sclerosis at whom within last 2 years the progression is not revealed.

To patients at whom stabilization of a course of a disease is not observed (for example, permanent progressing of a disease on EDSS scale within 6 months or need of carrying out 3 and more courses of therapy of corticotropin or GKS) during 1 year, drug of interferon beta 1b recommends to stop treatment.

Recommendations about use for patients:

1. Choose time of carrying out an injection, convenient for you. It is desirable for injection to do in the evening before going to bed.

2. Before administration of drug carefully wash up hands water with soap.

3. Take one blister strip packaging with the filled syringe/bottle from a cardboard pack which has to be stored in the refrigerator, and stand her at the room temperature within several minutes in order that temperature of drug was made even to air temperature. In case of condensate on a surface of a syringe/bottle wait some more minutes until condensate does not evaporate.

4. Before use it is necessary to examine solution in a syringe/bottle. In the presence of suspended particles or discoloration of solution or damage of the syringe / флакоиа drug should not be used. If there was a foam that happens when the syringe/bottle is stirred up or strongly shake, wait until foam accumulates.

5. Choose area of a body for an injection. Interferon beta 1b is entered into a hypodermic fatty tissue (a fatty layer between skin and muscular tissue) therefore use places with friable cellulose far from places of stretching of skin, nerves, joints and vessels:

- hips (the front surface of hips except a groin and a knee);

- a stomach (except a midline and okolopupochiy area);

- outside surface of shoulders;

- buttocks (upper outside quadrant).

It is not necessary to use for an injection the painful points decoloured, the reddened sites of skin or area with consolidations and small knots.

Every time choose the povy place for a prick, so you will be able to reduce unpleasant feelings and pain on the site of skin in the place of an injection. In each injection area there are many points for a prick. Constantly change points of injections in specific area.

6. Preparation for an injection.

If the patient uses drug of interferon beta 1b in syringes. Take the prepared syringe in a hand to which you write. Remove a protective cap from a needle.

If the patient uses drug of interferon beta 1b in bottles. Take a bottle with drug of interferon beta 1b and carefully put a bottle on a plain surface (table). Tweezers (or other convenient adaptation) uncover a bottle. Disinfect an upper part of a bottle. Take the sterile syringe in a hand to which you write, remove a protective cap from a needle and, without breaking sterility, carefully enter a needle through a rubber cap of a bottle so that the end of a needle (3-4 mm) was visible through bottle glass. Turn a bottle that its neck was directed down.

7. The amount of solution of drug interferon beta 1b which needs to be entered when carrying out an injection depends on the dose recommended by your doctor. You do not store the drug remains which remained in a syringe/bottle for repeated
uses.

If the patient uses drug interferon beta 1b in syringes. Depending on a dose which to you was prescribed by the doctor. To you can be required to remove the excess volume of solution of drug from the syringe. In case of such need slowly and accurately press the syringe piston for removal of excess amount of solution. You press on the piston until the piston does not reach a necessary tag on the label of the syringe.

If the patient uses drug interferon beta 1b in bottles. Slowly delay the piston back and gain in the syringe from a bottle the necessary volume of solution corresponding to a drug dose interferon beta lb which to you was prescribed by the doctor. Then, without breaking sterility, remove a bottle from a needle, holding a needle at the basis (you watch that the needle did not come off the syringe). Having turned the syringe a needle up, and, moving the piston, remove vials of air with careful percussion on the syringe and pressing on the piston. Replace a needle on the syringe and remove from it a cap.

8. Previously disinfect the site of skin where the drug interferon beta 1b will be administered. When skin dries, slightly collect skin pleated big and index by fingers.

9. Having the syringe perpendicular to the place of an injection, enter a needle into skin at an angle 90 °. The recommended depth of introduction of a needle makes 6 mm from the surface of skin. Depth is selected depending on type of a constitution and thickness of a hypodermic fatty tissue. You administer the drug, evenly pressing the syringe piston down to the end (to its full devastation).

10. Remove the syringe with a needle the movement vertically up.

11. Throw out the used syringes/bottles only to the specially allotted place unavailable to children.

12. If you forgot to administer the drug interferon beta 1b, make an injection immediately as soon as remembered it. The following injection is made in 48 h. It is not allowed to enter a double dose of drug. Do not stop drug use interferon beta 1b without consultation with the doctor.


Features of use:

Use at pregnancy and feeding by a breast. It is unknown whether interferon is capable beta 1b to cause damages of a fruit at treatment of pregnant women or to influence a pas reproductive function of the person. In controlled clinical trials at patients with multiple sclerosis misbirth cases were noted. In researches at macaques Rhesus factors human interferon beta 1b had embriotoksichesky effect and in higher doses caused increase in frequency of abortions. Therefore, interferon beta 1b is contraindicated during pregnancy. Women of reproductive age at treatment by this drug should use adequate methods of contraception. In case of approach of pregnancy during treatment by interferon beta 1b or pregnancy planning, the woman should be informed on potential risk and to recommend the treatment termination.

It is unknown whether interferon beta 1b with breast milk is excreted. Considering potentiality of development of serious undesirable reactions to interferon beta 1b at the babies who are on breastfeeding it is necessary to stop feeding by a breast or to cancel drug.

Use at abnormal liver functions. Use of drug is contraindicated at liver diseases in a decompensation stage.

Use for children. Drug use aged up to 18 years is contraindicated (information on efficiency and safety of use of interferon beta 1b at children is limited. Efficiency of use for children is not proved).

Special instructions. Pathology of immune system. Use of cytokines for patients with a monoclonal gammapathy sometimes was followed by development of a syndrome of system increase in permeability of capillaries with shocklike symptoms and a lethal outcome.

GIT pathology. In rare instances against the background of use of drug of interferon beta 1b development of the pancreatitis in most cases connected with existence of a gipertriglitseridemiya was observed.

Defeat of a nervous system. Patients need to be informed that the depression and suicide thoughts at which emergence it is necessary to see a doctor immediately can be side effect of drug of interferon beta 1b.

In two controlled clinical trials with participation of 1657 patients with the secondary progressing PC reliable distinctions of frequency of development of a depression and suicide thoughts at use of interferon were not revealed beta 1b or placebo. Nevertheless, it is necessary to show care at purpose of drug of interferon beta 1b the patient with depressive frustration and suicide thoughts in the anamnesis.

At emergence of the similar phenomena against the background of treatment, it is necessary to consider a question of expediency of drug withdrawal of interferon beta 1b.

Drug of interferon beta 1b needs to be used with care at patients with spasms in the anamnesis, including receiving therapy by antiepileptic drugs, especially if attacks at these patients are not controlled adequately against the background of therapy of grotivoepilepticheskim by drugs.

Changes of laboratory indicators. Patients with dysfunction of a thyroid gland are recommended to check function of a thyroid gland (hormones of a thyroid gland, thyritropic hormone) regularly, and in other cases - according to clinical indications.

Except the standard laboratory analyses appointed when maintaining patients with multiple sclerosis before therapy by drug of interferon beta 1b. and also it is regular during treatment, it is recommended to carry out the developed blood test, including definition of a leukocytic formula, both numbers of thrombocytes and biochemical analysis of blood, and also to check function of a liver (for example, activity of ACT, ALT and g-glutamiltraisferazy (g-GT)).

When maintaining patients with anemia, thrombocytopenia, a leukopenia (separately or in a combination) more careful monitoring of the developed blood test, including determination of quantity of erythrocytes, leukocytes, thrombocytes and a leukocytic formula can be required.

Disturbance from a liver and biliary tract. Clinical trials showed that therapy by interferon beta 1b can often lead to asymptomatic increase in activity of "hepatic" transaminases which, in most cases, is expressed slightly and has passing character. As well as at treatment by other interferona a beta severe damages of a liver (including a liver failure) at use of drug of interferon beta 1b are observed seldom. The most hard cases were celebrated at the patients who were affected by gepatotoksichny medicines or substances and also at some associated diseases (for example, malignant new growths with innidiation, heavy infections and sepsis, alcoholism).

At treatment by drug of interferon beta 1b it is necessary to carry out monitoring of function of a liver (including assessment of a clinical picture). Increase in activity of transaminases in blood serum demands careful observation and inspection. At substantial increase of activity of transaminases in blood serum or emergence of signs of damage of a liver (for example, jaundices) it is necessary to cancel drug. In the absence of clinical signs of damage of a liver or after normalization of activity of "hepatic" enzymes therapy resuming by drug of interferon beta 1b with observation of function of a liver is possible.

Disturbance from kidneys and urinary tract. At purpose of drug patients should be careful with a heavy renal failure.

Diseases of cardiovascular system. Drug of interferon beta 1b needs to be used with care at patients with heart diseases, in particular, at an ischemic heart disease, disturbances of a rhythm and heart failure. Monitoring of function of cardiovascular system, especially in an initiation of treatment has to be carried out.

There are no certificates in favor of direct cardiotoxic effect of interferon beta 1b, however, the grippopodobny syndrome connected using interferon beta 1b, can become a significant stressful factor for patients with the available significant pathology of cardiovascular system. During post-marketing observation very seldom there came the aggravation of symptoms of activity of cardiovascular system at patients with the available significant pathology of cardiovascular system which on time of emergence was connected with an initiation of treatment interferon beta 1b.

There are rare messages on emergence of a kardiomioiatiya against the background of treatment by drug of interferon beta 1b. At development of a cardiomyopathy. if it is supposed that it is connected using drug, then treatment by drug of interferon beta 1b should be stopped.

The general disturbances and disturbances in the place of an injection. Serious allergic reactions can be observed (rare, but shown in an acute and severe form, such as bronchospasm, anaphylaxis and urticaria). At the patients receiving drug of interferon beta 1b necrosis cases in the place of an injection were observed (see the section "Side effect"). The necrosis can be extensive and extend on muscular a fascia, and also fatty tissue and, as a result, lead to formation of hems. In certain cases removal of devitalized sites or, more rare, skin transplantation is necessary. Healing process at the same time can take up to 6 months.

At emergence of signs of damage of integrity of skin (for example, the expirations of liquid from the place of an injection) the patient should see a doctor before he continues performance of injections of drug of interferon beta 1b.

At emergence of the multiple centers of a necrosis treatment by drug of interferon beta 1b should be stopped before full healing of the damaged sites. In the presence of one center if the necrosis is not too extensive, use of drug of interferon beta 1b can be continued as at some patients healing of the devitalized site in the place of an injection happened against the background of use of drug of interferon beta 1b.

For the purpose of decrease in risk of development of reaction and a necrosis in the place of an injection, patients should recommend:

- to carry out injections, strictly following rules of an asepsis;

- every time to change the place of an injection;

- to administer the drug strictly п / to.

Periodically it is necessary to control correctness of performance of independent injections, especially at emergence of local reactions.

Immunogenicity. As well as at treatment the possibility of antibody formation exists any other drugs containing proteins at use of drug of interferon beta 1b. In a number of controlled clinical trials the analysis of blood serum was made each 3 months for identification of antibody formation to interferon beta 1b. In these researches it was shown that neutralized antibodies to interferon beta 1b developed at 23-41% of patients that was confirmed by at least two subsequent positive results of laboratory tests. At 43-55% from these patients in the subsequent laboratory researches stable lack of antibodies to interferon beta 1b was revealed.

In a research with participation of patients with clinically isolated syndrome allowing to assume multiple sclerosis, neutralized activity which was measured each 6 months during the corresponding visits was noted at 16.5-25.2% of the patients receiving interferon beta 1b. Neutralized activity was found, at least, once in 30% (75) patients receiving interferon beta 1b; at 23% (17) from them before the research came to the end, the status of antibodies became negative again.

During the two-year period of a research development of neutralized activity did not contact decrease in clinical performance (in what concerned time before clinically reliable multiple sclerosis).

It was not proved that existence of neutralized antibodies a little considerably influences clinical results. Emergence of any side reactions did not contact development of neutralized activity.

The decision on continuation or the termination of therapy has to be based on indicators of clinical activity of a disease, but not on the status of neutralized activity.

Influence on ability to manage vehicles, mechanisms. Special researches were not conducted. The undesirable phenomena from TsNS can influence ability to drive the car and to work with mechanisms. In this regard it is necessary to be careful at occupation potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. At emergence of the described side effects it is necessary to refrain from performance of the specified types of activity.


Side effects:

Undesirable reactions often arise at the initial stages of treatment, however, during the subsequent treatment their frequency and intensity decrease. The most frequent reactions are the grippopodobny symptom complex (fever, a fever, a joint pain, an indisposition, perspiration, a headache or muscle pain) and reactions in an injection site which are in many respects caused by pharmacological properties of interferon beta 1b. Reactions in an injection site often meet after use of interferon beta 1b: reddening, hypostasis, dekoloration, inflammation, pain, гиперчувствителыюсть, necrosis, нсспсцифичсскис reactions. For improvement of portability it is recommended to begin therapy with interferon beta 1b from titration (see the scheme of titration of a dose in the section "Dosing Mode"), the grippopodobny syndrome can be also corrected by purpose of NPVP. Prevalence of reactions in an injection site can be reduced at use of an autoinjector.

Lists of the undesirable phenomena revealed within clinical trials are given below (table 3. the undesirable phenomena and deviations of laboratory indicators), and according to post-registration use of interferon of run-1b (tab. 4, frequencies are calculated proceeding from the joint these clinical trials (very often (> 10%), it is frequent (<10%-> 1%), infrequently (<1%-> 0.1%), it is rare (<0.1%-> 0.01%) and it is very rare (<0.01%)). Experience of use of interferon beta 1b at patients with multiple sclerosis is limited, the undesirable reactions arising very seldom can be not revealed yet.

Table 3. The undesirable phenomena and deviations of laboratory indicators with an emergence frequency> 10% in comparison by the frequency of the corresponding phenomenon on placebo; the significant side effects connected with drug <10%.

System of bodies
Undesirable phenomena and deviations of laboratory indicators and deviation of laboratory indicators
Clinically isolated syndrome
(BENEFIT)
For the second time
the progressing multiple sclerosis (The European research)
For the second time
the progressing multiple sclerosis (Severoamerikanskoyesky research)
Recurrent multiple sclerosis
Interferon beta 1b
250 mkg (placebo)
n=292 (n=176)
Interferon beta 1b
250 mkg (placebo)
n=360 (n=358)
Interferon beta 1b
250 mkg (placebo)
n=317 (n=308)
Interferon beta 1b
250 mkg (placebo)
n=124 (n=123)
Infections
Infections 6% (3%) 13% (11%) 11% (10%) 14% (13%)
Abscess 0% (1%) 4% (2%) 4% (5%) 1% (6%)
Blood and lymphatic system
Lymphopenia (<1500/mm3) 1,2,4 79% (45%) 53% (28%) 88% (68%) 82% (67%)
Neutropenia (<1500/mm3) 1,2,3,4 11% (2%) 18% (5%) 4% (10%) 18% (5%)
Leukopenia (<3500/mm3) 1,2,3,4 11% (2%) 13% (4%) 13% (4%) 16% (4%)
Lymphadenopathy 1% (1%) 3% (1%) 11% (5%) 14% (11%)
Metabolic disturbances
Hypoglycemia (<55 mg/dl) 3% (5%) 27% (27%) 5% (3%) 15% (13%)
Mental disturbances
Depression 10% (11%) 24% (31%) 44% (41%) 25% (24%)
Alarm 3% (5%) 6% (5%) 10% (11%) 15% (13%)
Nervous system
Head bol2 27% (17%) 47% (41%) 55% (46%) 84% (77%)
Dizziness 3% (4%) 14% (14%) 28% (26%) 35% (28%)
Sleeplessness 8% (5%) 12% (8%) 26% (25%) 31% (33%)
Migraine 2% (2%) 4% (3%) 5% (4%) 12% (7%)
Paresthesias 16% (17%) 35% (39%) 40% (43%) 19% (21%)
Organs of sight
Konjyuktivit 1% (1%) 2% (3%) 6% (6%) 12% (10%)
Disturbances zreniya2 3% (1%) 11% (15%) 11% (11%) 7% (4%)
Acoustic organs
Ear pain 0% (1%) <1% (1%) 6% (8%) 16% (15%)
Diseases from heart
Feeling serdtsebiyeniya3 1% (1%) 2% (3%) 5% (2%) 8% (2%)
Vascular system
Vazodilatation 0% (0%) 6% (4%) 13% (8%) 18% (17%)
Arterial gipertenziya4 2% (0%) 4% (2%) 9% (8%) 7% (2%)
Bodies of a dyakhaniye
Upper respiratory tract infections 18% (19%) 3% (2%)    
Sinusitis 4% (6%) 6% (6%) 16% (18%) 36% (26%)
Cough 2% (2%) 5% (10%) 11% (15%) 31% (23%)
Odyshka3 0% (0%) 3% (2%) 8% (6%) 8% (2%)
GIT
Diarrhea 4% (2%) 7% (10%) 21% (19%) 35% (29%)
Lock 1% (1%) 12% (12%) 22% (24%) 24% (18%)
Nausea 3% (4%) 13% (13%) 32% (30%) 48% (49%)
Rvota2 5% (1%) 4% (6%) 10% (12%) 21% (19%)
Pains in zhivote4 5% (3%) 11% (6%) 18% (16%) 32% (24%)
Liver and zheltovyvodyashchy ways
Increase in ALT (> 5 times in comparison with initial) 1,2,3,4 18% (5%) 14% (5%) 4% (2%) 19% (6%)
Increase in nuclear heating plant (> 5 times in comparison with initial) 1,2,3,4 6% (1%) 4% (1%) 2% (1%) 4% (0%)
Skin and hypodermic - a fatty tissue
Skin reactions 1% (0%) 4% (4%) 19% (17%) 6% (8%)
Syp2,4 11% (3%) 20% (12%) 26% (20%) 27% (32%)
Disturbances from a musculoskeletal system
Gipertonus4 2% (1%) 41% (31%) 57% (57%) 26% (24%)
Mialgiya3,4 8% (8%) 23% (9%) 19% (29%) 44% (28%)
Myasthenia 2% (2%) 39% (40%) 57% (60%) 13% (10%)
Dorsodynia 10% (7%) 24% (26%) 31% (32%) 36% (37%)
Extremity pain 6% (3%) 14% (12%)   0% (0%)
Urinary system
Ischuria 1% (1%) 4% (6%) 15% (13%)  
Proteinuria (> 1)1 25% (26%) 14% (11%) 5% (5%) 5% (3%)
The speeded-up urination 1% (1%) 6% (5%) 12% (11%) 3% (5%)
Urine incontience 1% (1%) 8% (15%) 20% (19%) 2% (1%)
Imperative desires 1% (1%) 8% (7%) 21% (17%) 4% (2%)
Reproductive system
Dysmenorrhea 2% (0%) <1% (1%) 6% (5%) 18% (11%)
Disturbance menstrual cyclases 1% (2%) 9% (13%) 10% (8%) 17% (8%)
Metrorargiya 2% (0%) 12% (6%) 10% (10%) 15% (8%)
Impotence 1% (0%) 7% (4%) 10% (11%) 2% (1%)
The general reactions and reactions in an injection site
Reactions in an injection site (various types) 2,3,4,5 52% (11%) 78% (20%) 89% (37%) 85% (37%)
Necrosis in the place vvedeniya3 1% (0%) 5% (0%) 6% (0%) 5% (0%)
Grippopodobny sindrom3,4 44% (18%) 61% (40%) 43% (33%) 52% (48%)
Likhoradka2,3,4 13% (5%) 40% (13%) 29% (24%) 59% (41%)
Pain 4% (4%) 31% (25%) 59% (59%) 52% (48%)
Pain in grudi4 1% (0%) 5% (4%) 15% (8%) 15% (15%)
Peripheral hypostasis 0% (0%) 7% (7%) 21% (18%) 7% (8%)
Asteniya3 22% (17%) 63% (58%) 64% (59%) 49% (35%)
Oznob2,3,4 5% (1%) 23% (7%) 22% (12%) 46% (19%)
Potlivost3 2% (1%) 6% (6%) 10% (10%) 23% (11%)
Nedomoganiye3 0% (1%) 8% (5%) 6% (2%) 15% (3%)

1 Deviation of a laboratory indicator
2 It is authentically connected with therapy by interferon beta 1b at patients from PUSSYCATS, р <0.05
3 It is authentically connected with therapy by run-1b interferon at patients with RRS. р <0.05
4 It is authentically connected with therapy by interferon beta 1b at patients with VPRS, р <0.05
5 Reactions in an injection site can include any adverse manifestations arising in the place of an injection, for example: bleeding in the place of an injection, hypersensitivity, an inflammation in the place of an injection, a swelling in an injection site, a necrosis in the place of an injection, pain in the place of an injection. hypostasis in the place of injections, and an atrophy in the place of an injection; "Grpppopodobiyn a syndrome" designates a combination at least, two of the symptoms given below: fever, fever, mialgiya, indisposition, perspiration.

Table 4. (Frequency is specified according to the given classification: very often (> 10%). often (<10%-> 1%). infrequently (<1%-> 0.1%), it is rare (<0.1%-> 0.01%) and is very rare (<0.01%)). Experience of use of interferon beta 1b at patients with multiple sclerosis is limited, the undesirable reactions arising very seldom can be not revealed yet (data are based on the registered spontaneous messages).

Class of system of bodies Very often ≥1/10 Often ≥1/100 to <1/10 Not often ≥1/1000 to <1/100 Seldom ≥1/10000 to <1/1000 Very seldom <0.01%
Blood and lymphatic system   Anemia Thrombocytopenia Bleeding **  
Disturbances from immune system       Anaphylactic reactions Syndrome of a hyperpermeability of capillaries in the presence of a monoclonal gammapathy
Endocrine disturbances   Hypothyroidism   Hyperthyroidism
Pathology of a thyroid gland
 
Metabolic disturbances   Increase in weight
Weight reduction
Increase in level of triglycerides of blood Anorexia  
Mental disturbances   The confused consciousness Emotional lability
Suicide attempts
   
Disturbances from a nervous system     Spasms    
Disturbances from heart   Tachycardia   Cardiomyopathy  
Vascular disorders     Hypertensia Decrease in the ABP **  
Disturbances from respiratory system, a thorax and a mediastinum     Bronchospasm    
Disturbances from a GIT       Pancreatitis  
Disturbances from a gepatobiliarny path   Increase in level of bilirubin of blood Increase in level gamma глутаминтраспептидазы
Hepatitis
Disturbances of a liver, including hepatitis
Liver failure
 
Skin and hypodermic fatty tissue   Small tortoiseshell
Itch
Alopecia
Skin discoloration    
Disturbances from a musculoskeletal system and connecting fabric Arthralgia        
Disturbances from reproductive system and milk glands   Menorrhagia      

* frequency is established in clinical trials
** data of CJSC Biokard


Interaction with other medicines:

Special researches of interaction of interferon beta 1b with other drugs were not conducted.

The effect of use of interferon beta 1b in a dose of 8 million ME every other day on metabolism of medicines at patients with multiple sclerosis is unknown.

Against the background of use of interferon beta 1b GKS and AKTG appointed for a period of up to 28 days at treatment of aggravations are transferred well. Use of interferon beta 1b along with other immunomodulators (except GKS or AKTG) was not studied.

Iptsrferona reduce activity of mikrosomalyiy liver enzymes of system of P450 cytochrome at the person and animals. It is necessary to be careful at purpose of interferon beta 1b in a combination with the drugs having a narrow therapeutic index which clearance substantially depends on activity of these enzymes (including antiepileptic means, antidepressants).

It is also necessary to be careful at simultaneous use of any drugs influencing system of a hemopoiesis.

Researches on compatibility with antiepileptic drugs were not conducted.


Contraindications:

— hypersensitivity to recombinant ipterferonu-beta or to other components of drug;

liver diseases in a decompensation stage;

— a serious depressive illness and/or suicide thoughts in the anamnesis;

epilepsy (adequately not controlled);

— pregnancy;

— children's age up to 18 years (information on efficiency and safety of use of interferon beta 1b at children is limited. Efficiency of use for children is not proved).

Patients in whose anamnesis there is an instruction on a depression or spasms and also to the patients receiving irotivosudorozhny means, interferon beta 1b should apply with care. Drug should be used with care at patients with heart failure of the III-IV stage on classification of NYHA and at patients with a cardiomyopathy. It is necessary to be careful at treatment by drug interferon beta lb of patients with dysfunctions of marrow, anemia or thrombocytopenia.


Overdose:

Interferon beta 1b in doses to 176 million ME by 3 times a week did not cause the serious undesirable phenomena in adult patients with malignant tumors.


Storage conditions:

Drug should be stored in the place, nelrstupny for children, at a temperature from 2 °C to 8 °C. A period of validity - 2 years. Within an established period of the validity storage by the patient of not opened bottle/syringe within one month at a temperature not above 25 °C is admissible. Not to apply after the period of validity specified on packaging.


Issue conditions:

According to the recipe


Packaging:

0.5 ml - syringes (1) - planimetric strip packagings (1) (complete with napkins spirit No. 1) - packs cardboard.
0.5 ml - syringes (1) - planimetric strip packagings (5) (complete with napkins spirit No. 5) - packs cardboard.
0.5 ml - syringes (1) - planimetric strip packagings (15) (complete with napkins spirit No. 15) - packs cardboard.



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