Interferon beta 1b

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.

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%.

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).

* 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.