Infibeta

General characteristics. Structure:

Active agent: interferon beta 1b – 0,3 mg (there correspond 9,6 million ME);

Excipients: albumine human – 15 mg, Mannitolum – 15 mg.

1 bottle with solvent contains: chloride sodium solution of 0,54% for injections.

1 ml of solvent contains: sodium chloride – 5,4 mg, water for injections – to 1 ml.

Pharmacological properties:

Pharmacodynamics. Interferon beta 1b has antiviral and immunomodulatory activity. The mechanism of effect of interferon beta 1b at scattered

sclerosis (RS) it is not finalized. 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 reduces the connecting ability of a receptor of interferon g and increases its internalization and degradation. Besides, interferon beta 1b increases suppressor activity of mononuclear cells of peripheral blood.

Both at remittiruyushchy, and at the secondary progressing multiple sclerosis treatment by interferon beta 1b reduces frequency (by 30%) and weight of clinical exacerbations of a disease, number of hospitalization and the need for treatment by glucocorticosteroids, and also extends remission duration.
Patients with the secondary progressing RS have a treatment by interferon beta 1b further progressing of a disease and approach of disability, including heavy (i.e. when patients are forced to use constantly a wheelchair) for a period of up to 12 months allows to detain. This effect is observed at patients both with exacerbations of a disease, and without aggravations, and also with any index of an invalidism (patients with assessment from 3 to 6,5 points on an expanded scale of assessment of a condition of an invalidism participated in a research).
Results of a magnetic and resonant tomography of a brain sick with the remittiruyushchy and secondary progressing multiple sclerosis against the background of treatment with interferon beta 1b confirm considerable positive influence of drug on weight of pathological process, and also considerable reduction of formation of the new active centers.

Pharmacokinetics. After hypodermic introduction by interferon beta 1b in the recommended dose of 0,25 mg serumal concentration of interferon beta 1b low or are not defined at all. In this regard data on pharmacokinetics interferon beta 1b at the patients with multiple sclerosis receiving drug in the recommended dose no.

After hypodermic introduction of 0,5 mg of drug the maximum concentration of interferon beta 1b in plasma is reached in 1–8 h after an injection and makes about 40 ME/ml. Absolute bioavailability of interferon beta 1b at hypodermic introduction — about 50%. At intravenous administration of drug the clearance and an elimination half-life of interferon beta 1b from serum average 30 ml/min. and 5 h respectively.

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

At hypodermic administration of drug in a dose of 0,25 mg every other day the maintenance of markers of the biological answer (neopterine, β2-микроглобулин and immunosuppressive cytokine, interleykin-10) considerably increases in comparison with initial indicators in 6–12 h after introduction of the first dose of drug. Concentration of these substances reached maximum in 40–124 h and remained raised throughout 7-day (168 h) the research period.

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.

The Remittiruyushchy Multiple Sclerosis (RMS) — for reduction of frequency and weight of aggravations at ambulatories (i.e. the patients capable to go without assistance) in the presence in the anamnesis not less than 2 aggravations 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 expressed by deterioration in neurologic functions within the last two years — for reduction of frequency and severity of clinical exacerbations of a disease, and also for delay of rates of progressing of a disease.

Route of administration and doses:

Treatment by the drug ИнфибетаÒ should be begun under observation of the doctor having experience of treatment of multiple sclerosis.

Now there is unresolved a question of therapy duration the drug ИнфибетаÒ.
For remittiruyushchy multiple sclerosis the available data confirm preservation of efficiency of treatment by the drug ИнфибетаÒ for 5 years. For the secondary progressing multiple sclerosis in controlled clinical trials sufficient data for confirmation of efficiency of treatment within two years and limited data on efficiency for the 3-year period of treatment were obtained.

For patients with the only clinical episode which is presumably a symptom of multiple sclerosis, efficiency was shown during the 5-year period.

Preparation of injection solution
For dissolution of the lyophilized powder of interferon beta 1b for injections use enclosed the ready syringe with solvent and the adapter for a bottle with a needle.

It is not necessary to use the damaged bottle.
With the drug Infibeta enter 1,2 ml of solvent (solution of sodium of chloride of 0,54%) into a bottle. Powder has to be dissolved completely without stirring. Before use it is necessary to examine ready solution. In the presence of particles or discoloration of solution it cannot be applied. 1 ml of ready solution contains 250 mkg (8 million ME) of interferon beta 1b. After preparation of injection solution gain in the syringe necessary quantity for an injection according to the titrated dose.

Subcutaneously.
Dosing mode
The recommended dose of the drug ИнфибетаÒ 250 of mkg (8 million ME) which contains in 1 ml of the prepared solution is entered subcutaneously every other day. In an initiation of treatment it is usually recommended to carry out titration of a dose.
Treatment it is necessary to begin with introduction 62,5 mkg (0,25 ml) subcutaneously every other day, gradually increasing the dose to 250 mkg (1,0 ml) entered also every other day. The period of titration of a dose can vary depending on individual portability of drug.
The table for titration of a dose *

Day of treatment	Dose, mkg	Volume drug, ml
1, 3, 5	62,5	0,25
7, 9, 11	125	0,5
13, 15, 17	187,5	0,75
≥19	250	1

* the scheme of titration of a dose which was used in a research at patients with the only clinical episode of demyelination allowing to assume multiple sclerosis is submitted.
At patients with recurrent remittiruyushchim a sclerosis which for last 2 years had less than two aggravations or at patients to the secondary progressing multiple sclerosis at whom within last two years the disease was in an inactive phase use of drug is not recommended.

Patients at whom improvement is not observed (for example, permanent progressing of a disease on EDSS scale within 6 months or need of carrying out three and more courses of therapy of corticotropin or glucocorticosteroids) the drug ИнфибетаÒ are recommended to stop treatment.

Features of use:

Immune disturbances
Use of cytokines for patients with a monoclonal gammapathy sometimes was followed by system increase in permeability of capillaries with development of shock and a lethal outcome.

Gastrointestinal disturbances
In rare instances against the background of use of the drug ИнфибетаÒ the development of 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 the drug ИнфибетаÒ.
In two controlled clinical trials with participation of 1657 patients with the secondary progressing RS reliable distinctions of frequency of development of a depression and suicide thoughts at use of interferon were not revealed beta 1b or placebo. Nevertheless, patients should show care at purpose of the drug ИнфибетаÒ 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 ИнфибетаÒ.
The drug ИнфибетаÒ needs to be used with care at patients with spasms in the anamnesis.

This drug contains human albumine, and for this reason there is very insignificant risk of transfer of viral diseases. The theoretical risk of transfer of a disease of Kreyttsfeldta-Jacob is also considered extremely improbable.

Changes of laboratory indicators
Except the standard laboratory analyses appointed when maintaining patients with multiple sclerosis before therapy by the drug ИнфибетаÒ, and also regularly during performing treatment it is recommended to carry out the developed blood test, including definition of a leukocytic formula, number of thrombocytes and biochemical analysis of blood, and also to check function of a liver (for example, activity of aspartate aminotransferase (nuclear heating plant), alaninaminotranspherase (ALT) and g-glutamiltransferazy (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.

Disturbances 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 is in most cases expressed slightly and has passing character.

As well as at treatment by other interferona the beta, severe damages of a liver (including a liver failure) at use of the drug ИнфибетаÒ 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 the drug ИнфибетаÒ 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 the drug ИнфибетаÒ 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.

Endocrine disturbances
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.

Diseases of cardiovascular system
The drug ИнфибетаÒ needs to be used with care at patients with heart diseases, in particular, at heart failure of the III-IV functional class on classification of the New York Cardiological Association (NYHA).
If against the background of treatment by the drug ИнфибетаÒ the cardiomyopathy develops and it is supposed that it is connected using drug, then treatment by the drug ИнфибетаÒ 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 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 the drug ИнфибетаÒ.

At the patients receiving the drug ИнфибетаÒ necrosis cases in the place of an injection were observed (see the section "Side effects").
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 the multiple centers of a necrosis treatment by the drug ИнфибетаÒ 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 the drug ИнфибетаÒ can be continued as at some patients healing of the devitalized site in the place of an injection happened against the background of drug ИнфибетаÒ use.

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 subcutaneously.

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, with containing proteins, at use of the drug ИнфибетаÒ. 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) of the 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.

Use for children
Systematic studying of efficiency and safety of the drug ИнфибетаÒ at children and teenagers up to 18 years it was not carried out.

Influence on ability to manage vehicles and to work with 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.

Corrected preparation of solution for subcutaneous injections
For preparation of solution for hypodermic introduction drug (lyophilisate) is dissolved in solvent, carrying out rules of an asepsis in the course of preparation and administration of solution. For this purpose perform the following procedures:

· carefully wash hands with warm water with soap;
· remove plastic slips from each bottle;
· process rubber bungs a napkin spirit;
· carefully open the blister packaging of the syringe and a long needle, having unbent a paper covering to the middle;
· put on a long needle the syringe, remove a protective cap from a needle;
· puncture with a long needle a rubber bung of a bottle with solvent and select all solution;
· carefully delete vials of air from the syringe;
· carefully open the blister packaging of the second long needle;
· take out the filled syringe from a needle, leaving it in a stopper of an empty bottle;
· put on the second long needle the syringe filled with solvent remove a protective cap from a needle;
· puncture a rubber bung of a bottle with lyophilisate, directing a needle to a bottle sidewall, and slowly enter solvent on a bottle wall, avoiding foaming and contact of a needle with drug solution;
· careful rocking dissolve bottle contents, avoiding stirring;
· look through the prepared drug solution in the passing light to be convinced of lack of not dissolved particles and/or mechanical inclusions.
Not to use solution if it muddy, changed color or contains visible particles;
· select the prepared solution in the syringe to a tag of "1,0 ml" (no more), inclining a bottle so that the end of a long needle constantly remained in solution,
· take out the syringe from a needle, leaving it in a bottle stopper;
· carefully open the blister packaging of a short needle;
· accurately put on a short needle with a protective cap the syringe.

Carrying out a subcutaneous injection
1. Choose the place for injections.
· ИнфибетаÒ it is entered subcutaneously into the soft tissues located far from joints and nerves. Places for injections have to be located in the following areas:
- Hands (back surface of a shoulder).
- A stomach (excepting area of a navel and waist).
- Buttocks.
- Hips (a front and side surface, excepting area of a groin and knee).

Places for injections need to be alternated, choosing every time the new place. It will allow skin to be recovered, prevent hit of an infection and development of local reactions. For example, if the first injection was made in the right half of a stomach, then make the second in the left half, the third – in the right hip, etc. For convenience write down where and when injections are made.
· Do not do an injection to places where hillocks, swellings, firm nodes or pain are felt. It is not necessary to do injections to sites of skin of the changed color, and also in the presence of crusts, deepenings or damages. At detection at yourself similar changes see a doctor.
· If it is difficult for you to reach any place, ask to help the person who is able to do injections.
2. Wipe skin in the place of an injection with a spirit napkin and wait when skin dries.
3. Accurately remove a protective cap from a short needle.
4. Carefully remove vials of air from the syringe.
5. Carefully you zashchipnit skin in the place of an injection big and index fingers to raise a little it.
6. Sharp confident movement enter the hypodermic needle directly into the raised site of skin at an angle 90º.
7. Slowly enter all solution which is contained in the syringe (no more than 1,0 ml) evenly pressing on the piston.
8. Press a spirit napkin to the place of an injection and remove a needle from skin.
9. Massage the place of an injection a napkin spirit.
10. Remove the syringe, needles and bottles in a container for the fulfilled materials.

Solution of drug is used right after preparation. If the injection is postponed, storage of the prepared solution in the syringe or a bottle is allowed no more than 3 hours at a temperature from 2 to 8 °C.

Side effects:

The undesirable phenomena observed with a frequency at 2% and above than in group of placebo (inactive drug) at patients who during clinical trials received interferon beta 1b in a dose of 0,25 mg or 0,16 mg/sq.m every other day duration up to three years are listed below.
Grippopodobny symptoms can be weakened, using non-steroidal anti-inflammatory drugs.

Experience of use of interferon beta 1b for treatment of patients with multiple sclerosis is rather limited, therefore, the negative reactions arising with a low frequency could not be observed yet.

For the description of specific reaction, its synonyms and states connected with it the most suitable term from the Medical dictionary for regulatory activity (MedDRA) is used.

General reactions
Reaction in the place of an injection, an adynamy (weakness), a complex of grippopodobny symptoms, a headache, fervescence, a fever, peripheral hypostasis, a stethalgia, pain of various localization, a febricula, a necrosis in the place of an injection.

Cardiovascular system
Increase in arterial pressure.

Alimentary system
Abdominal pain.

Blood and lymphatic system
Lymphocytopenia <1500/mm3, neutropenia <1500/mm3, leukopenia <3000/mm3; lymphadenopathy.

Metabolic and alimentary disturbances
Increase in activity of enzymes in blood: aspartate aminotransferases (nuclear heating plant) by 5 times from a reference value, alaninaminotranspherase (ALT) by 5 times from a reference value.

Musculoskeletal system
Myasthenia, mialgiya, spasms in legs.

Nervous system
Sleeplessness, incoordination.

Respiratory system
Asthma.

Skin
Rash, damage of skin.

Urinogenital system
To an urination, women have imperative desires a metrorrhagia (acyclic uterine bleedings), men have an impotence.

The list of side effects given below is based on observation of use of drug after entry into the market.
Frequency of side effects is classified as follows:
very often (≥10%), it is frequent (<10% — ≥1%), infrequently (<1% — ≥0,1%), is rare (<0,1% — ≥0,01%) and is very rare (<0,01%).

General reactions
Very often: grippopodobny symptoms (fever, a fever, mialgiya, a headache or the increased perspiration) *. Frequency of these symptoms decreases over time.
Seldom: febricula, stethalgias, decrease in body weight, increase in body weight.

Local reactions
Very often: reactions in the place of an injection (a hyperemia, local swelled) *, an inflammation *, боль*.
Often: a necrosis in the place инъекции*.
Over time at treatment continuation the frequency of reactions in a drug injection site usually decreases.

Blood and lymphatic system
Infrequently: anemia, thrombocytopenia, leukopenia.
Seldom: lymphadenopathy.

Endocrine disturbances
Seldom: dysfunctions of a thyroid gland, including hyperthyroidism, hypothyroidism.

Metabolic disturbances
Seldom: increase in concentration of triglycerides.

Nervous system
Infrequently: muscle hyper tone, depression.
Seldom: spasms, confusion of consciousness, excitement, emotional lability, suicide attempts, anorexia, dizziness.

Cardiovascular system
Infrequently: increase in arterial pressure.
Seldom: cardiomyopathy, tachycardia, strong heartbeat.
Very seldom: vazodilatation.

Respiratory organs
Seldom: asthma, bronchospasm.

Digestive tract
Infrequently: nausea and vomiting.
Seldom: pancreatitis, diarrhea.

Liver and biliary tract
Infrequently: increase in activity of nuclear heating plant, ALT in blood.
Seldom: increase in activity of g-glutamiltransferazy, concentration of bilirubin in blood, hepatitis.

Skin and hypodermic cellulose
Infrequently: alopecia, urticaria, skin itch, skin rashes.
Seldom: skin discoloration.

Skeletal muscles
Infrequently: mialgiya.
Seldom: arthralgia.

Female reproductive system
Seldom: disturbances of a menstrual cycle.
Very seldom: menorrhagia (long menstrual bleedings).

Allergic reactions
Seldom: anaphylactic reactions.

* frequency is specified on the basis of these clinical trials.

Interaction with other medicines:

Use of interferon beta 1b along with other immunomodulators, in addition to glucocorticosteroids or corticotropin, was not studied.

It is necessary to be careful at use of interferon beta 1b in combination with other medicines which metabolism is carried out by certain isoenzymes of P450 cytochrome. Some concern this group widely febrifugal and sedatives, antidepressants, anticonvulsant drugs. It is also necessary to be careful at simultaneous use of any drugs influencing system of a hemopoiesis.

If during the long period it is necessary to accept in addition any drugs, it is necessary to see a doctor.

In view of lack of researches on compatibility, this medicine it is not necessary to mix with other medicines.

Contraindications:

Hypersensitivity to drug components, pregnancy, the breastfeeding period, children's age up to 18 years.
Heavy depression and (or) suicide thoughts.
Dekompensirovanny liver failure.

With care
Heart diseases, in particular, heart failure of the III-IV functional class on classification of the New York Cardiological Association (NYHA), a cardiomyopathy;
spasms in the anamnesis;
monoclonal gammapathy;
anemia, thrombocytopenia, leukopenia;
abnormal liver function.

Pregnancy and period of breastfeeding
Pregnancy
It is unknown whether interferon is capable beta 1b to cause disturbances in a fruit at treatment of pregnant women or to influence 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 misbirths. Women of reproductive age at treatment by this drug should use reliable methods of contraception. In case of approach of pregnancy during treatment by the drug ИнфибетаÒ or when planning pregnancy the woman has to be informed on potential risk; drug is recommended to be cancelled.

Breastfeeding period
It is unknown whether interferon beta 1b with breast milk is emitted. Considering a theoretical possibility of development of undesirable reactions to interferon beta 1b at the children who are on breastfeeding it is necessary to stop feeding by a breast or to cancel drug.

Overdose:

At administration of the drug ИнфибетаÒ intravenously in a dose to 5500 mkg (176 million ME) three times a week to adult patients with oncological diseases were not revealed the serious undesirable phenomena.
Against the background of use of interferon beta 1b the glucocorticosteroids and corticotropin appointed for a period of up to 28 days at treatment of aggravations are transferred well.

Storage conditions:

At a temperature from 2 to 8 °C. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for hypodermic introduction in the glass bottles corked by rubber bungs with a running in caps aluminum-plastic with control of the first opening.

On 1,2 ml of solvent in the glass bottles corked by rubber bungs with a running in caps aluminum-plastic with control of the first opening.

5 bottles with drug or 5 bottles with solvent in a blister strip packaging from a film polyvinyl chloride.

1 or 3 blister strip packagings with drug and 1 or 3 blister strip packagings with solvent complete with 5 or 15 syringes, 10 or 30 needles (long) for solution preparation, 5 or 15 needles (short) for hypodermic introduction, 10 or 30 napkins spirit and the application instruction in a pack from a cardboard.

Each syringe and needle are placed in sterile one-time packaging from a film polyvinyl chloride and the paper laminated.

Napkins spirit are separated by a divider cardboard.

On a joint of a cover and a front side of a pack the self-adhesive unmarked label for control of the first opening is pasted.