Ронбетал®

General characteristics. Structure:

Active ingredient: 8 million ME or 16 million ME of interferon beta 1b human recombinant.

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

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

Pharmacological properties:

Pharmacodynamics. Interferon beta 1b has antiviral and immunomodulatory activities. Effect of interferon beta 1b at multiple sclerosis is caused by linkng with high-affine receptors on a surface of a cell and start of an expression of a number of the proteins possessing antiviral, anti-proliferative and antiinflammatory action.

The therapeutic effect of interferon beta 1b at multiple sclerosis is caused by the shift of tsitokinovy balance of advantage of antiinflammatory cytokines, braking of proliferation of leukocytes and disturbance of the presentation of autoantigens. The important mechanism of effect of interferon beta 1b is decrease in rate of migration of leukocytes through a blood-brain barrier due to decrease in an expression of the metalproteases increasing permeability of a blood-brain barrier. Interferon beta 1b reduces the connecting ability and an expression of receptors to interferon - gamma, and also strengthens their disintegration.

Thus, interferon beta 1b is an antagonist of interferon - the gamma, playing an important role in a pathogeny multiple sclerosis. Besides, interferon beta 1b increases suppressor activity of mononuclear cells of peripheral blood and reduces resistance of T lymphocytes to apoptosis, causing death of autoreactive clones.
 
Pharmacokinetics. After hypodermic administration of interferon beta 1b in the recommended dose of 0,25 mg 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 hypodermic introduction of 0,5 mg of interferon beta 1b the maximum levels in plasma make about 40 ME/ml through 1-8ch after an injection. Absolute bioavailability of interferon beta 1b at hypodermic introduction equals about 50%.

At intravenous use of interferon beta 1b the clearance and an elimination half-life of drug from serum averages 30 ml/min. and 5 hours, respectively. 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 hypodermic 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:

Ронбетал® it is applied for:
• reduction of frequency and weight of aggravations at patients with a recurrent remittiruyushchim the course of multiple sclerosis;
• for delay of rates of progressing of a disease at patients with the secondary progressing course of multiple sclerosis.
To apply strictly on doctor's orders!

Route of administration and doses:

Ронбетал® enter subcutaneously every other day in a dose 8 million ME. Not to stir up and use solution at once. Repeated injections to the same site of skin are undesirable.

Prolonged treatment (long-term). In controlled clinical trials the effect of treatment by interferon beta 1b remained within 3 years of observations.

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.

Features of use:

Treatment is carried out under control of the doctor. 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 therapy by interferon beta 1b. In rare instances these states can lead to suicide attempts. In the presence of a depression and suicide thoughts it is necessary to stop therapy immediately.

To purpose of interferon beta 1b and against the background of treatment it is necessary to carry out regularly developed blood test, including definition of a leukocytic formula, and also to define activity of nuclear heating plant, ALT and GGT. In case of increase in activity of transaminases in blood serum it is necessary to make careful observation and inspection of the patient. Drug needs to be cancelled at substantial increase of activity of liver enzymes or emergence of symptoms of hepatitis. In the absence of clinical signs of injury of a liver after normalization of level of liver enzymes it is possible to discuss a question of resuming of therapy under careful control of function of a liver.

There are no data on use of Ronbetala® for patients with the broken function of a liver and kidneys.

In clinical trials at a part of patients with multiple sclerosis emergence of the serumal antibodies neutralizing interferon beta 1b was noted. Influence of antibody formation on clinical performance of interferon beta 1b is studied now. The available results are contradictory and do not allow to draw an unambiguous conclusion. Signs of negative influence of neutralized antibodies on delay of progressing of a disease at the secondary progressing multiple sclerosis are not revealed.

At the patients receiving interferon beta 1b necrosis cases in the place of an injection are described. The area of a necrosis can be extensive and deep. At emergence of the multiple centers of a necrosis treatment by interferon beta 1b should be stopped before their full healing which can continue up to 6 months. In the presence of one center and a condition of lack of an extensive necrosis, treatment by interferon beta 1b can be continued.

To reduce risk of development of a necrosis in the place of an injection, patients should recommend:
 
• to follow rules of an asepsis when performing injections;
• to constantly change places of an injection.

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

If communication of a cardiomyopathy, развывшейся in the course of treatment, with therapy by interferon beta 1b is supposed, treatment should be stopped.

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.

Pregnancy and lactation. It is unknown whether interferon is capable beta 1b 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 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.

Side effects:

During registration clinical trial of the drug Ronbetal® the following undesirable phenomena were observed.

General reactions: complex of grippopodobny symptoms, fervescence, fever.

Local reactions: reaction in the place of an injection, morbidity in the place of an injection.

Cardiovascular system: increase in arterial pressure.

Blood and lymphatic system: anemia, lymphopenia.

Metabolic and alimentary disturbances: increase in level of enzymes in blood: increase in the TTG level, aspartate aminotransferase (nuclear heating plant) to 4 times from initial, alaninaminotranspherases (ALT) to 4 times from initial.

Nervous system: alarming states.

Musculoskeletal system: mialgiya.

Skin: rash of makulezno-papular character.

At use of other drugs of interferon beta 1b the following undesirable phenomena were observed.

The general disturbances and reactions in an injection site: reaction in the place of an injection, an adynamy (weakness), a complex of grippopodobny symptoms, a headache, fervescence, a fever, an abdominal pain, a stethalgia, pain of various localization, a febricula, a necrosis in the place of an injection.

Cardiovascular system: peripheral hypostasis, vazodilatation, diseases of peripheral vessels, hypertensia, strong heartbeat, tachycardia.

Alimentary system: nausea, lock, diarrhea, dispeptic phenomena.

Blood and lymphatic system: lymphopenia <1500/mm3, neutropenia <1500/mm3, leukopenia <3000/mm3. Lymphadenopathy.

Metabolic and alimentary disturbances: increase in level of enzymes in blood: aspartate aminotransferases (nuclear heating plant) by 5 times from initial, alaninaminotranspherases (ALT) by 5 times from initial. Increase in body weight.

Musculoskeletal system: a myasthenia, an arthralgia, a mialgiya, spasms in legs.

Nervous system: hyper tone, dizziness, sleeplessness, incoordination, concern, nervousness.

Respiratory system: asthma.

Skin: rash, skin diseases, the increased sweating, an alopecia.

Urinogenital system: to an urination, the speeded-up urination, women have imperative desires a metrorrhagia (acyclic bleedings), a menorrhagia (long menstrual bleedings), a dysmenorrhea (painful monthly), men have an impotence, prostate diseases.

In post-market researches the following side effects of other drugs of interferon beta 1b were registered (frequency of side effects is classified as follows: very often (≥10%), it is rather 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, fever, mialgiya, headache or perspiration). Frequency of these symptoms decreases over time. Seldom: febricula, stethalgias, decrease in body weight.

Local reactions: very often: reactions in the place of an injection (a hyperemia, local hypostasis), an inflammation, pain. Infrequently: skin necrosis. 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: dysfunction of a thyroid gland, hyperthyroidism, hypothyroidism.

Metabolic disturbances: seldom: increase in level of triglycerides.

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

Cardiovascular system: infrequently: arterial hypertension. Seldom: cardiomyopathy, tachycardia, heartbeat.

Respiratory organs: seldom: asthma, bronchospasm.

Digestive tract: infrequently: nausea and vomiting. Seldom: pancreatitis.

Liver and biliary tract: infrequently: increase in activity of nuclear heating plant, ALT. Seldom: increase in activity of GGT, bilirubin level, hepatitis.

Skin and hypodermic cellulose: infrequently: alopecia, urticaria, skin itch, skin rashes. Seldom: skin discoloration, the increased perspiration.

Skeletal muscles: infrequently: mialgiya.

Female reproductive system: seldom: disturbances of a menstrual cycle.

Allergic reactions: seldom: anaphylactic reactions.

Interaction with other medicines:

At treatment of exacerbations of a disease the patients receiving interferon beta 1b, had a good portability of corticosteroids or AKTG which applied for up to 28 days.

Use along with other immunodepressants, except corticosteroids or AKTG, was not studied. Ying-terferony reduced activity hepatic cytochrome of P450-dependent enzymes at the person and animals.

It is necessary to be careful at appointment in a combination with the drugs having a narrow therapeutic index which clearance substantially depends on hepatic system of P450 cytochrome (for example, antiepileptic means).

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

Contraindications:

• Hypersensitivity to recombinant interferon - to beta or 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.

With care. To patients in whose anamnesis there is an instruction on a depression or spasms and also to the patients receiving anticonvulsants, it is necessary to apply Ronbetal® 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 the drug Ronbetal® of patients with dysfunctions of marrow, anemia or thrombocytopenia.

Due to the insufficiency of data on use, care at appointment is necessary for patients more young than 18 years.

Overdose:

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

Storage conditions:

At a temperature from 2 to 8 °C. Storage within one month at a temperature up to 25 °C is admissible. In the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic introduction of 8 million ME/ml on 1 ml in bottles of colourless glass corked by rubber bungs with a running in aluminum caps. On 5 or 10 bottles in a blister strip packaging from a PVC film. 1 or 3 strip packagings with the application instruction in a pack from a cardboard.

Solution for hypodermic introduction of 8 million ME/0,5 of ml on 0,5 ml in ternary sterile syringes from colourless neutral glass. On 1 syringe in a blister strip packaging from a PVC film. 1, 5 or 15 strip packagings with the application instruction in a pack from a cardboard.

The pack with bottles is in addition completed:

• syringes one-time injection insulin with a needle 26G of H 12 mm of 1,0 ml on 5, 10, 15 and 30 pieces respectively;
• needles of medical injection 30G H 13 mm on 5, 10, 15 and 30 pieces respectively;
• needles of medical injection 29G H 8 mm on 5, 10, 15 and 30 pieces respectively;
• napkins spirit on 10, 20, 30 and 60 pieces respectively.
The pack with syringes is in addition completed:
• napkins spirit on 1, 5 and 15 pieces respectively.