Betaferon

General characteristics. Structure:

Interferon a beta - lb (IFN-a beta - lb) - 0,30 mg (there correspond 9,6 million ME) albumine human, Mannitolum
1 ml of the prepared solution contains 0,25 mg (8,0 million ME) of recombinant interferon beta lb.
1 ml of water solvent for preparation of solution for injections contains 5,4 mg of sodium of chloride.

Description. Lyophilisate: The lyophilized mass of white color. Solvent: Transparent almost colourless solution.
The recovered solution: Solution from slightly opalescent to opalescent, colourless or light yellow color.

Pharmacological properties:

Pharmacodynamics. Active agent of drug Betaferon (interferon beta lb) has antiviral and immunomodulatory activity. Mechanisms of effect of interferon beta 1b at the multiple sclerosis (MS) are 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 with these receptors induces an expression of a number of substances which are considered as mediators of biological effects of interferon beta 1К Keeping of some of these substances was defined in serum and fractions of the sick cells receiving interferon beta 1К Interferon beta 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.
Both at remittiruyushchy, and at the secondary progressing multiple sclerosis treatment by Betaferon 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.
At patients with the secondary progressing RS treatment by Betaferon allows to detain 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. This effect nablyudtsya at patients both with exacerbations of a disease, and without aggravations, and also with any index of an invalidism (patients with assessment from 3,0 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 by Betaferon confirm considerable positive influence of drug on weight of pathological process, and also considerable reduction of formation of the new active centers.
Toxicological property
Researches of acute toxicity were not conducted. As rodents are insensitive to effect of human interferon a beta, assessment of risk was carried out on the basis of toxicity researches at repeated doses at macaques Rhesus factors. The tranzitorny hyperthermia, along with the expressed passing increase in concentration of lymphocytes and passing decrease in thrombocytes and segmentoyaderny neutrophils was observed.
Long researches of toxicity were not conducted. Researches of reproductive toxicity at macaques Rhesus factors revealed toxicity for mother and increase in frequency of spontaneous abortions. At live posterity any malformations were not observed. Researches of influence on fertility were not conducted. Any influence on an estrous cycle of monkeys was not observed.
In one separate research of genotoxicity (Ames's test), any mutagen effects were not observed. Researches of carcinogenicity were not conducted. The test of cellular transformation in vitro did not reveal any cancerogenic potential.

Pharmacokinetics. After hypodermic introduction of Betaferon 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 drug pharmacokinetics at the patients with multiple sclerosis receiving Betaferon in the recommended dose no.
After hypodermic introduction of 0,5 mg of Betaferon the maximum concentration in plasma dosigatsya in 1-8 h after an injection and makes about 40 ME/ml. Absolute bioavailability of Betaferon at hypodermic introduction - about 50%. At intravenous administration of interferon beta 1b the clearance and an elimination half-life of drug from serum average 30 ml/min. and 5 hours respectively.
Betaferon's introduction every other day does not lead to increase in concentration of interferon of beta lb in a blood plasma, and its pharmacokinetics during a course of therapy does not change.
At hypodermic use of Betaferon in a dose of 0,25 mg every other day the maintenance of markers of the biological answer (neopterine, beta2-microglobulin and immunosuppressive cytokine, interleykin-10) considerably raises 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.

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 the clinically reliable multiple sclerosis (CRMS) 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> 9 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
MPT.
• 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 Betaferon should be begun under observation of the doctor having experience of treatment of multiple sclerosis.
Now there is unresolved a question of duration of therapy by Betaferon. In clinical trials treatment duration at patients with the remittiruyushchy and secondary progressing multiple sclerosis reached 5 and 3 years respectively. Duration of a course is defined by the doctor.
Preparation of injection solution
A. The drug packaging containing bottles and previously filled syringes:
For dissolution of the lyophilized powder of interferon beta 1Ь for injections use enclosed the ready syringe with solvent and a needle.
B. The drug packaging containing bottles, previously filled syringes, the adapter for a bottle with a needle and spirit napkins:
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.
With Betaferon 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 0,25 mg (8 million ME) of interferon beta lb.
Route of administration
Subcutaneously
Dosage
The recommended Betaferon's dose of 0,25 mg (8 million ME) which contains in 1 ml of the prepared solution is entered subcutaneously every other day.
If you forgot to give an injection in due time, then you need to administer to yourself the drug at once as soon as you remembered it. The following injection is made in 48 h.

Features of use:

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 Betaferon, 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 gamma глутамилтрансферазы (u-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.
Gastrointestinal disturbances
In rare instances against the background of Betaferon's use the development of pancreatitis in most cases connected with existence of a gipertriglitseridemiya was observed.
Abnormal liver function and biliary tract
Clinical trials showed that therapy by Betaferon 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 Betaferon's use 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, an alcohol abuse).
At treatment by Betaferon 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 resuming of therapy by Betaferon with observation of function of a liver is possible.
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
Betaferon it is necessary to apply with care at patients with heart diseases, in particular, at heart failure of the III-IV stage on classification of the New York Cardiological Association (NYHA) as such patients were not included in clinical trials.
If against the background of treatment by Betaferon the cardiomyopathy develops and it is supposed that it is connected using drug, then treatment by Betaferon should be stopped.
Diseases 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 Betaferon.
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 Betaferon's use or placebo were not revealed. Nevertheless, patients should show care at Betaferon's appointment 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 cancellation of Betaferon.
Betaferon it is necessary to apply with care at patients with spasms in the anamnesis.
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 Betaferon.
At the patients receiving Betaferon necrosis cases in the place of an injection were observed (see. "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 Betaferon should be stopped before full healing of the damaged sites. In the presence of one center if the necrosis is not too extensive, Betaferon's use can be continued as at some patients healing of the devitalized site in the place of an injection happened against the background of Betaferon's 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.

 

Neutralized antibodies
As well as at treatment the possibility of antibody formation exists any other drugs with protein content, at Betaferon's use. In a number of controlled clinical trials the analysis of blood serum was made each 3 months for identification of antibody formation to Betaferon. In these researches it was shown that neutralized antibodies to interferon beta lb 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 lb 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 16,5k25,2 by % of the patients receiving Betaferon. Neutralized activity was found, at least, once in 30% (75) of the patients receiving Betaferon; 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.
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.
Use for children
Systematic studying of efficiency and Betaferon's safety at children and teenagers up to 18 years it was not carried out.
Influence on ability to drive the car 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 requiring special attention.

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 Betaferon in a dose 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 Betaferon 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 Increase in Arterial Pressure system.
• 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.
• A musculoskeletal system the Myasthenia, a mialgiya, spasms in legs.
• Nervous system Sleeplessness, incoordination.
• Respiratory Asthma system.
• 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 Betaferon's use after entry into the market.
Frequency of side effects is classified as follows: very often (> 10%), it is frequent (<10%-> 1%), infrequently (1% <-> of 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.
Seldom: increase in activity gamma глутамилтрансферазы, concentration of bilirubin, 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:

Special researches of interaction of Betaferon with other drugs were not conducted.
The effect of use of Betaferon in a dose of 0,25 mg (8 million ME) every other day on metabolism of medicines at patients with multiple sclerosis is unknown.
Against the background of Betaferon's use the glucocorticosteroids and AKTG appointed for a period of up to 28 days at treatment of aggravations are transferred well. Betaferon's use along with other immunomodulators, in addition to corticosteroids or AKTG, was not studied.
Interferona reduce activity hepatic cytochrome of P450-dependent enzymes at the person and  animals. It is necessary to be careful at Betaferon's appointment in a combination with the medicines having a narrow therapeutic index which clearance substantially depends on hepatic system of P450 cytochrome (for example, antiepileptic means, antidepressants). It is also necessary to be careful at simultaneous use of any drugs influencing system of a hemopoiesis.
In view of lack of researches on compatibility, this medicine it is not necessary to mix with other medicines.

Contraindications:

• Pregnancy.
• Lactation.
• Reactions of hypersensitivity to natural or recombinant interferon - beta or human albumine in the anamnesis.

Use with care
Betaferon it is necessary to apply with care at patients with the following diseases:
• heart diseases, in particular, heart failure of the III-IV stage on classification of the New York Cardiological Association (NYHA), a cardiomyopathy;
• depressions and suicide thoughts (including in the anamnesis), epileptic seizures in the anamnesis;
• monoclonal gammapathy;
• anemia, thrombocytopenia, leukopenia;
• abnormal liver function.
Due to the lack of sufficient experience of use care at use for patients is necessary more young than 18 years.

Pregnancy and lactation
• Pregnancy
It is unknown whether Betaferon is capable to cause damages of 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 a Rhesus factor human interferon бета-^ had embriotoksichesky effect and in higher doses caused increase in frequency of abortions. Women of reproductive age at treatment by this drug should use reliable methods of contraception. In case of approach of pregnancy during treatment by Betaferon or pregnancy planning, it is recommended to cancel drug.
• Lactation
It is unknown whether interferon beta 1b with breast milk is emitted. Considering a theoretical possibility of development of undesirable reactions to Betaferon in the babies who are on breastfeeding it is necessary to stop feeding by a breast or to cancel drug.

Overdose:

At Betaferonbetaferon's introduction intravenously in a dose to 5,5 mg (176 million ME) three times a week to adult patients with oncological diseases were not revealed the serious undesirable phenomena.

Storage conditions:

At a temperature not above 25 °C. Not to freeze. To store in the place, unavailable to children. Period of validity.
Lyophilisate - 2 years. Solvent - 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for hypodermic introduction on 9,6 million ME of drug in a bottle from glass like I (Evr. Pharm.) with the stopper rolled by an aluminum cap with the unsnapped cover of turquoise color.
1) Solvent (solution of sodium of chloride of 0,54%) on 1,2 ml in the syringe from glass like I (Evr. Pharm.) in a strip packaging PVC/paper (blister).
5 bottles in the plastic pallet and 5 syringes (everyone in the blister) together with the application instruction in a cardboard box or 15 bottles in the plastic pallet and 15 syringes (everyone in the blister) together with
  the application instruction in a cardboard box

2) Solvent (solution of sodium of chloride of 0,54%) on 1,2 ml in the syringe from glass like I (Evr. Pharm.).
1 bottle, 1 syringe, 1 adapter with a needle for a bottle and 2 spirit napkins place in the one-time cardboard packaging having a cardboard insert.
On 5 or on 15 one-time packagings together with the application instruction in a cardboard box.