Interferon beta-1b - instructions for use, dose, side effects, contraindications

Active substanceInterferon beta-1bInterferon beta-1b

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Dosage form: & nbspSolution for subcutaneous administration.

Composition:

1 ml of the solution contains:

active substance: interferon beta 1-b human recombinant (rchIFN-beta) - 8 million ME or 16 million ME

Excipients: sodium acetate trihydrate 0.408 mg, glacial acetic acid to pH 4.0, dextran 50 to 70 to 15 mg, polysorbate 80 to 0.04 mg, mannitol 50 mg, disodium edetate dihydrate 0.05555 mg , water for injection - up to 1 ml.

Description:Transparent, colorless or yellowish liquid.

Pharmacotherapeutic group:Cytokine. Means for treating multiple sclerosis.

ATX: & nbsp

L.03.A.08 Interferon beta-1b

Pharmacodynamics:Recombinant interferon beta-lb is isolated from Escherichia coli cells, into the genome of which the human interferon beta beta gene encoding the amino acid of the series in the 17th position. Interferon beta-lb is a non-glycosylated protein of a molecular weight of 18500 daltons, consisting of 165 amino acids.

Pharmacodynamics

Interferons are proteins in their structure and belong to the family of cytokines. The molecular weight of interferons is in the range from 15,000 to 21,000 Daltons.There are three main classes of interferons: alpha, beta and gamma. Interferons alpha, beta and gamma have a similar mechanism of action, however, different biological effects. The activity of interferons is species-specific, and therefore, it is only possible to study their effects on human cell cultures or in vivo on the person.

Interferon beta-lb has antiviral and immunomodulating activities. The mechanism of action of interferon beta-lb with multiple sclerosis is not fully established. However, it is known that the biological effect of interferon beta-lb is mediated by its interaction with specific receptors that are found on the surface of human cells. Binding of interferon beta-lb with these receptors induces the expression of a number of substances that are considered as mediators of the biological effects of interferon beta-lb. The content of some of these substances was determined in the serum and blood cell fractions of patients who received interferon beta-lb. Interferon beta-lb reduces the binding capacity of the interferon gamma receptor and improves its internalization and degradation. In addition, interferon beta-lb increases the suppressor activity of peripheral blood mononuclear cells.

There have been no targeted studies to determine the impact of

interferon beta-lb on the function of the cardiovascular system, respiratory and

endocrine systems.

Results of clinical trials

Remittent Multiple Sclerosis:

As part of a controlled clinical trial, patients with a remitting form of multiple sclerosis capable of independent walking (EDSS from 0 to 5.5) who received interferon beta-lb, Data were obtained that the drug reduces the frequency of exacerbations by 30%, reduces the severity of exacerbations and the number of hospitalizations due to the underlying disease. Further, the interval between exacerbations and the tendency to slow the progression of remitting multiple sclerosis were shown.

Secondary-progressive multiple sclerosis:

Two controlled clinical trials were conducted, involving 1657 patients with a secondarily progressive form of multiple sclerosis. Patients with a baseline value EDSS from 3 to 6.5 points, i.е. patients were able to walk independently.In assessing the main endpoint of the study, "time to the confirmed progression," i.e. the ability to slow the progression of the disease in studies, conflicting data were obtained. One of two studies showed a statistically significant slowdown in the rate of progression of disability (the ratio of risks = 0.69 at 95% confidence interval (0.55, 0.86), p = 0.0010, risk reduction was 31% in the interferon beta-lb) and increase the time until the loss of the opportunity to move independently, i.e. use of a wheelchair or EDSS 7.0 (risk ratio = 0.61 at 95% confidence interval (0.44, 0.85), p = 0.0036, risk reduction was 39% in the interferon beta therapy group,lb) among patients who took interferon beta-lb. The therapeutic effect of the drug persisted in the subsequent period of observation, regardless of the frequency of exacerbations.

In a second study of interferon beta-lb In patients with a secondarily progressive form of multiple sclerosis, slowing of the rate of progression is not indicated. However, the patients included in this study had less disease activity than patients in other studies with a secondary progression of multiple sclerosis.A retrospective meta-analysis of the data from both studies showed a statistically significant effect (p = 0.0076, when comparing groups of patients who received interferon beta-lb 8M ME, and placebo groups).

A retrospective analysis of subgroups showed that the effect on the rate of progression was more pronounced in the group of patients with high disease activity prior to initiation of therapy (risk ratio = 0.72 at 95% confidence interval (0.59, 0.88), p = 0.0011, risk reduction was 28% in the group patients with exacerbations or rapid progression EDSS, who received interferon beta-lb, in comparison with the placebo group). Based on the results of the analysis, we can conclude that the analysis of the frequency of relapses and rapid progression EDSS (EDSS> 1 point or> 0.5 at the base EDSS>6 points for previous therapy for two years) can help identify patients with active disease. In these studies, a decrease in the frequency of exacerbations (30%) was also shown. It has not been shown that interferon beta-lb has an effect on the duration of exacerbations.

Clinically isolated syndrome:

One controlled clinical study of interferon beta-lb were performed in patients with clinically isolated syndrome (CIC). CIS countries suggest a single clinical episode of demyelination and / or at least two clinically unresponsive foci on T2-weighted images of MRI that are not sufficient to diagnose a clinically significant PC. It is established that the CIS is more likely to lead to the development of multiple sclerosis. The study included patients with one clinical focus or two or more foci on MRI, provided that all alternative diseases that could be the most likely cause of the symptoms other than multiple sclerosis were excluded.

This study consisted of two phases, a placebo-controlled phase and a follow-up phase. The placebo-controlled phase had a duration of 2 years or until the patient switched to clinically significant multiple sclerosis (CVDD). After completing the placebo-controlled phase, the patient was transferred to the follow-up phase against interferon beta therapy,lb. In order to assess the early and delayed effect of the assignment of interferon beta-lb compared groups of patients originally randomized to interferon beta-lb (immediate care group) and placebo (deferred treatment group). During the study, patients and researchers remained blinded to the distribution of patients in treatment groups.

Table 1. Efficacy of interferon beta-lb in clinical trials BENEFIT and prolonged follow-up of study patients BENEFIT.

	2 years		Results of the 3rd year		The results of the 5-
	of therapy		of therapy		th year of observation
	Placebo-		Subsequent phase		Subsequent phase
	controlled phase		open therapy		open therapy
	Interferon beta-lb 8 million ME	Placebo	Group immediately th treatment with interferon beta- lb 8 million ME n=292	A group of delayed treatment with interferon beta-lb 8 million ME	Group immediate treatment with interferon beta-lb 8 million ME	Group of delayed treatment with interferon beta-1 b 8 million IU
	n=292	n=176		n=176	n=292	n=176
Number	271 (93%)	166	249	143 (81%)	235 (80%)	123 (70%)
patients		(94%)	(85%)
completed
this phase
Key Performance Indicators
Time to development of clinically reliable multiple sclerosis (CVD)
According to Kaplan-Mayer	28%	45%	37%	51%	46%	57%
Risk reduction	47% vs. placebo		41% in comparison with the group of delayed treatment with interferon beta-1b		37% in comparison with the group of delayed treatment with interferon beta-1b
risk ratio at 95% CI	HR = 0.53 [0.39,0.73]		HR = 0.59 [0.42.0.83]		HR = 0.63 [0.48.0.83]
Log- rank test	pO.OOOl interferon beta-lb prolonged the time to the onset of CVD for 363 days, from 255 days in the placebo group (up to 618 days in the interferon beta-lb)		P = 0.0011		Р = 0.0027
Time before transformation in PC by the criteria of McDonald
According to Kaplan-Mayer	69%	85%	Not the main endpoint		Not the main endpoint
Risk reduction	43% compared with placebo
risk ratio at 95% CI	HR = 0.57 [0.46,0.71]
Log- rank test	p <0.000l
Time to progression EDSS
According to Kaplan-	Was not the main		16%	24%	25%	29%
Mayer	the endpoint
Decrease			40% compared to		24% in comparison with
risk			group of delayed treatment with interferon beta-1 b		group of delayed treatment with interferon beta-1 b
attitudes			HR = 0.60 [0	39,0.92]	HR = 0.76 [0.52,1.11]
risks at 95% CI
Log-			P = 0.022		P = 0.177
ranked
test

In the placebo-controlled phase of the study, interferon beta-lb statistically reliably prevented the transition of the CIS into the KDRS. In the group of patients who received interferon beta-lb, a delay in the transformation into reliable multiple sclerosis according to the McDonald criteria (see Table 1).

Analysis of subgroups, depending on the initial factors, demonstrated the effectiveness of interferon beta-lb in relation to the prevention of transformation in the CDC in all subgroups. The risk of transformation into CVD within 2 years was higher in the group of patients with monofocal CIS with 9 or more foci on T2-weighted images or with the presence of foci accumulating contrast, according to MRI data at the beginning of the study. The effectiveness of interferon beta-lb in the group of patients with multifocal clinical manifestations did not depend on the baseline MRI, which indicates a high risk of transformation of CIS into CVD in patients of this group.

Currently, there is no generally accepted definition of high risk, but patients with a mono-ICC (clinical manifestation of 1 focal point in the central nervous system) and at least 9 foci on MRI in T2-mode and / or accumulating contrast medium can be classified as a high risk group. Patients with multifocal CIS (clinical manifestations> 1 center in the central nervous system) are at high risk of developing KDRS regardless of the number of lesions on MRI. In any case, the decision to prescribe interferon beta-lb should be taken, based on the conclusion about the high risk of development of CVD in the patient.

Therapy with interferon beta-lb was well tolerated by patients, as indicated by a low percentage of dropouts (93% completed the study).

To improve the tolerance, titration of the interferon beta-lb, non-steroidal anti-inflammatory drugs were used at the beginning of therapy. In addition, the auto-injector was used in the majority of patients throughout the study.

Further, interferon beta-lb maintained high efficiency in their ability to prevent the development KDRS after 3 and 5 years of follow-up (Table. 1), despite the fact that the majority of patients receiving placebo, initiated therapy with interferon beta-lb two years after the start of the study. Confirmed progression EDSS (increase EDSS, at least one visit in comparison with the initial value) was lower in the immediate treatment (Table. 1, revealed a significant effect on the 3rd year of therapy, but at the 5th no effect). The majority of patients in both groups had no disability progression over the 5-year period. No convincing evidence to support the impact on the outcome of the immediate appointment of interferon betalb. The effect of immediate treatment with interferon beta-lb on the quality of life of patients.

Remittent, secondary-progressive multiple sclerosis and clinically isolated syndrome:

Efficacy of interferon beta-lb is shown in all clinical studies on the ability to reduce the activity of the disease (acute inflammation in the central nervous system and persistent tissue damage) assessed by magnetic resonance imaging (MRI). The ratio of the clinical activity of multiple sclerosis and the activity of the disease according to MRI scores is not yet fully established.

Pharmacokinetics:

After subcutaneous administration of interferon beta-lb at a recommended dose of 8 million IU, its serum concentrations are low or not at all determined. In this regard, there is no information on the pharmacokinetics of the drug in patients with multiple sclerosis receiving interferon beta-lb at the recommended dose. After subcutaneous administration of 16 million IU of interferon beta-lb, the maximum plasma levels are about 40 IU / ml 1-8 hours after the injection.

According to the results of numerous clinical studies, the clearance of interferon beta-lb and the half-life of the drug from serum averages 30 ml / min / kg and 5 hours, respectively.The absolute bioavailability of interferon beta-lb with subcutaneous administration is approximately 50%.

The administration of interferon beta-lb every other day does not lead to an increase in the level of the drug in the blood plasma, and its pharmacokinetics during the course of therapy does not appear to change.

When subcutaneous application of interferon beta-lb at a dose of 0.25 mg every other day, the levels of biological response markers (neopterin, beta2-microglobulin and immunosuppressive cytokine interleukin-10) significantly increased in comparison with the baseline values 6-12 hours after the administration of the first dose of the drug. They peaked at 40-124 h and remained elevated during the 7-day (168 h) study period. The relationship between plasma levels of interferon beta-lb or the levels of markers induced by it and the mechanism of action of interferon beta-lb in multiple sclerosis has not been established.

Indications:

- Clinically isolated syndrome (CIC) (the only clinical episode of demyelination that allows presuming multiple sclerosis, with the exclusion of alternative diagnoses) with a sufficient degree of inflammation for the appointment of intravenous corticosteroids - to slow the transition to clinically significant multiple sclerosis (CVD) in patients at high risk of developing CDSO.

There is no generally accepted definition of high risk. According to the study, patients with a single-focus CIS (clinical manifestations of one focal point in the central nervous system) and >T2-foci on MRI and / or accumulated foci of foci. Patients with multifocal CIC (clinical manifestations> 1 foci in the central nervous system) belong to the group of high risk of developing CVD, regardless of the number of foci on MRI;

- Remitting multiple sclerosis - to reduce the frequency and severity of exacerbations of multiple sclerosis in patients who can walk without assistance, in the presence of at least 2 exacerbations of the disease in the past 2 years, followed by a complete or incomplete recovery of the neurological deficit;

- Secondary-progressive multiple sclerosis with an active course of the disease, characterized by exacerbations or pronounced impairment of neurologic functions in the last two years - to reduce the frequency and severity of clinical exacerbations of the disease, and to slow the progression of the disease.

Apply strictly according to the doctor's prescription.

Contraindications:

- Hypersensitivity to recombinant interferon-beta or other components of the drug.

- Diseases of the liver in the stage of decompensation.

- Severe depressive illness and / or suicidal thoughts in the anamnesis.

- Epilepsy (adequately not controlled).

- Pregnancy.

- Children under 18 years of age (Information on the efficacy and safety of interferon beta-lb in children is limited, and the effectiveness of use in children is not proven).

Carefully:Patients who have a history of depression or convulsions, as well as patients receiving anticonvulsants, interferon beta-lb should be used with caution. The drug should be used with caution in patients with heart failure III-IV stage according to NYHA classification and in patients with cardiomyopathy. Care should be taken when treating interferon beta-lb patients with impaired bone marrow function, anemia, or thrombocytopenia.

Pregnancy and lactation:It is not known whether interferon beta-lb is able to cause fetal damage in the treatment of pregnant women or affect the reproductive function of a person.In controlled clinical trials in patients with multiple sclerosis have been cases of spontaneous abortion. Studies in rhesus monkeys human interferon beta-lb has embryotoxic effects in higher doses, causes an increase in the frequency of abortion. Therefore, interferon beta-lb is contraindicated during pregnancy. Women of reproductive age in the treatment of this drug should use adequate methods of contraception. In case of pregnancy during treatment with interferon beta-lb or planning a pregnancy, a woman should be informed about the potential risks and recommend discontinuation of treatment. It is not known whether interferon beta-lb is excreted in breast milk. Given the potential for serious adverse reactions to Interferon beta-lb in infants who are breast-fed, you must stop breast-feeding or stop the drug.

Dosing and Administration:

Treatment with interferon beta-lb should be started under the supervision of a doctor,

who has experience in treating multiple sclerosis.

Adults:

The recommended dose of interferon beta-lb 8M ME administered subcutaneously every other day. Children:

There have been no formal clinical and pharmacokinetic studies in children and adolescents. Limited published data indicate a comparable safety profile of interferon beta-lb in a dose of 8 million ME subcutaneously every other day in a group of patients between 12 and 16 years of age, compared with the adult population. There is no information on the use of interferon beta-lb in persons under 12 years of age, the drug can not be used in this group of patients.

At the beginning of treatment, it is usually recommended to titrate the dose. Treatment should begin with the introduction of 2 million ME subcutaneously every other day, gradually increasing the dose to 8 million ME, which is also administered every other day. The period of titration of the dose may vary depending on the individual tolerability of the drug.

Table 2. Diagram of dose titration *

		The volume of the drug, ml, depending on
Day of treatment	Dose, million ME	of the applicable release form
Day of treatment	Dose, million ME	8 million IU / 0.5 mL	8 million IU / 1 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 titration period can be increased by the development of unwanted reactions.

The duration of treatment is not currently established. There are results of clinical studies,in which the duration of treatment in patients with remitting and secondary-progressive multiple sclerosis reached 5 and 3 years, respectively. In the group of patients with a relapsing course of multiple sclerosis, high efficacy is shown during the first two years. Further three-year follow-up showed the preservation of efficacy indicators throughout the treatment period. Patients with clinically isolated syndrome experienced a significant delay in transformation into reliable multiple sclerosis for more than five years.

Therapy with interferon beta-lb is not indicated in patients with a relapsing-remitting form of multiple sclerosis who have had less than two exacerbations in the past 2 years, or patients with a secondary progressive multiple sclerosis who have not progressed during the past two years.

Patients in whom there is no stabilization of the course of the disease (eg, persistent progression of the disease on a scale EDSS for 6 months or the need for three or more courses of corticotropin therapy or glucocorticosteroids) for 1 year, treatment with interferon beta-lb it is recommended to stop. Recommendations for use in patients:

1) Choose the time of your injection convenient for you. Injections should be done in the evening before bedtime.

2) Wash hands thoroughly with soap and water before you start the treatment.

3) Take one out-of-the-box package with a filled syringe / vial of cardboard pack that should be stored in the refrigerator and let it sit at room temperature for a few minutes so that the temperature of the drug is equal to the ambient temperature. In case of condensation on the surface of the syringe / vial, wait a few more minutes until the condensation evaporates.

4) Before use, inspect the solution in a syringe / vial. In the presence of suspended particles or a discoloration of the solution or damage to the syringe / vial, the drug should not be used. If there is foam, which happens, when the syringe / vial is shaken or strongly shakes, wait until the foam settles.

5) Select the area of the body for injection. Interferon beta-lb is injected into the subcutaneous fatty tissue (the fat layer between the skin and the muscle tissue),so use places with loose fiber away from stretch areas of the skin, nerves, joints and vessels (Figures 1 and 2 indicate recommended areas for injections):

- Hips (anterior thighs other than the groin and knee);

- The abdomen (except the midline and the near-pustular region);

- The outer surface of the shoulders;

- Buttocks (upper outer quadrant).

Do not use painful points, discolored, reddened areas of the skin or areas with seals and nodules for injection. Each time, choose a new site for the injection, so you can reduce discomfort and pain on the skin area at the injection site. Within each injection area, there are many points for the injection. Constantly change injection points within a specific area.

6) Preparation for injection.

If the patient is using interferon beta-lb in syringes

Take the prepared syringe in the hand that you are writing. Remove the protective cap from the needle.

If the patient is using interferon beta-lb in vials

Take a vial of interferon beta-lb and gently place the vial on a flat surface (table). Tweezers (or other convenient device), remove the lid of the vial.Disinfect the top of the vial. Take a sterile syringe into the hand that you are writing, remove the protective cap from the needle and, without violating sterility, carefully insert the needle through the rubber cap of the bottle so that the tip of the needle (3-4 mm) is visible through the glass of the vial. Turn the bottle over so that its neck is pointing down.

7) The amount of solution of the drug interferon beta-lb, which must be introduced when

injection depends on the dose recommended by your doctor. Do not store the remnants of the drug,

remain in the syringe / vial, for re-use.

If the patient is using interferon beta-lb in syringes

Depending on the dose that the doctor prescribed to you, you may need to remove the excess

volume of the drug solution from the syringe. If necessary, slowly and accurately

press the plunger of the syringe to remove excess solution. Push the piston to

As long as the piston does not reach the required mark on the syringe label.

If the patient is using interferon beta-lb in vials

Slowly pull the piston back and draw into the syringe from the vial the required volume of the solution,

corresponding to the dose of interferon beta-lb, which you prescribed a doctor. Then, without violating

sterility, remove the bottle from the needle, holding the needle at the base (make sure that the needle does not

jumped off the syringe). Turn the syringe upside down with a needle, and, moving the piston, remove air bubbles

cautiously tapping on the syringe and pressing on the piston. Replace the needle on the syringe and

remove the cap from it.

8) Pre-disinfect skin area where the drug interferon beta

lb. When the skin dries, slightly gather the skin into the fold with the thumb and forefinger (Fig. 3).

9) With the syringe perpendicular to the injection site, insert the needle into the skin at an angle of 90 ° (Figure 4).

The recommended insertion depth is 6 mm from the skin surface. Depth is selected in

depending on the type of constitution and thickness of subcutaneous fat. Introduce the drug,

evenly pressing the plunger of the syringe down to the end (until it is completely emptied).

10) Remove the syringe with the needle vertically upwards.

11) Dispose of used syringes / vials only in a specially designated place, which is inaccessible to children.

12) If you forget to inject interferon beta-lb, inject immediately as soon as you remember it. The next injection is given after 48 hours. Do not administer a double dose of the drug.

Do not stop using interferon beta-lb without consulting your doctor.

Side effects:

Undesirable reactions often occur during the initial stages of treatment, however, in the course of subsequent treatment, their frequency and intensity decrease. The most frequent reactions are the flu-like symptom complex (fever, chills, joint pain, malaise, sweating, headache or muscle pain) and reactions at the injection site, which are largely due to the pharmacological properties of interferon beta-lb. Reactions at the site of injection often occur after the use of interferon beta-lb: redness, swelling, decoloration, inflammation, pain, hypersensitivity, necrosis, nonspecific reactions. To improve the tolerability, it is recommended to begin interferon beta-lb therapy with titration (see the dose titration scheme in the "Dosage and Administration" section), the flu-like syndrome can also be adjusted by the appointment of non-steroidal anti-inflammatory drugspreparations. The prevalence of reactions at the injection site can be reduced by using an autoinjector.

Below are lists of adverse events identified in clinical trials (Table 3 adverse events and laboratory abnormalities), and according to the post-registration application interferon beta-lb (tab. 4, the frequency calculated based on combined clinical data (very often (> 10%), often (<10% - > 1%), infrequently (<1% - > 0.1%), rarely (<0.1% - > 0.01%) and very rarely (<0.01%)). Experience with the use of interferon beta-lb in patients with multiple sclerosis is limited, undesirable reactions that occur very rarely, may not yet have been identified.

Table 3. Undesirable phenomena and deviations of laboratory indicators with frequency of occurrence >10% compared with the frequency of the corresponding phenomenon on placebo; significant side effects associated with the drug <10%.

System of organs Adverse events and deviations laboratory indicators
		Clinically isolated syndrome (BENEFIT)		Secondary progressive absent-minded sclerosis (European study)		Secondary progressive absent-minded Sclerosis (North American study)		Recurrent multiple sclerosis
		Interferon beta-lb 250 mcg (placebo) n=292(n=176)		Interferon beta- lb 250 mcg (placebo) n=360 (n=358)		Interferon beta-1b 250 mcg (placebo) n=317 (n=308)		Interferon beta-lb 250 mcg (placebo) n=124 (n=123)
Infections
Infections		6% (3%)		13% (11%)		11% (10%)		14% (13%)
Abscess		0%(1%)		4% (2%)		4% (5%)		1 % (6 %)
Blood and lymphatic system
Lymphopenia (<1500 / mm³) * ^ o		79% (45%)		53% (28%)		88% (68%)		82% (67%)
Neutropenia (<1500 / mm³) ^X^ * o		11% (2%)		18% (5%)		4% (10%)		18 % (5 %)
Leukopenia (<-3000 mm³) ^X^ * o		11% (2%)		13% (4%)		13% (4%)		16% (4)%
Lymphadenopathy		1%(1%)		3%(1 %)		11% (5%)		14 % (11 %)
Metabolic disorders
Hypoglycemia (<55 mg / dL)^X		3% (5%)		27% (27%)		5% (3%)		15 %(13 %)
Mental disorders
Depression		10% (11%)		24% (31%)		44% (41%)		25% (24%)
Anxiety		3% (5%)		6% (5 %)		10% (11%)		15 % (13 %)
Nervous system
Headache ^		27% (17%)		47% (41%)			55% (46%)	84 % (77 %)
Dizziness		3% (4%)		14% (14%)			28% (26%)	35 % (28 %)
Insomnia		8% (4%)		12% (8%)			26% (25%)	31 % (33 %)
Migraine		2% (2%)		4% (3 %)			5% (4%)	12% (7%)
Paresthesia		16% (17%)		35% (39%)			40% (43%)	19% (21%)
The organs of sight
Conjunctivitis		1%(1%)		2% (3 %)		6% (6%)		12% (10%)
Visual impairment ^		3%(1%)		11% (15%)		11% (11%)		7% (4%)
Hearing organs
Ear pain		0% (1 %)			<1 % (1 %)	6% (8%)		16% (15%)
Diseases from the heart
Heart palpitations *	1% (1%)			2% (3 %)		5% (2%)		8 % (2 %)
Vascular system
Vasodilation			0% (0%)		6% (4%)	13% (8%)		18% (17%)
Hypertension			2% (0%)		4% (2 %)	9% (8%)		7 % (2 %)
Respiratory system
Upper respiratory tract infections		18% (19%)		3% (2%)
Sinusitis		4% (6%)		6 % (6%)		16% (18%)		36 % (26 %)
Cough		2% (2%)		5% (10%)		11% (15%)		31% (23%)
Shortness of breath *		0% (0%)		3% (2 %)		8% (6%)		8 % (2 %)
Gastrointestinal tract
Diarrhea		4% (2%)		7% (10%)		21% (19%)		35 % (29 %)
Constipation		1%(1%)		12% (12 %)		22% (24%)		24% (18%)
Nausea		3% (4%)		13% (13%)		32% (30%)		48% (49%)
Vomiting ^		5%(1%)		4% (6 %)		10% (12%)		21 % (19 %)
Stomach ache ^about		5% (3%)		11% (6%)		18% (16%)		32 % (24 %)
Liver and bile ducts
Increase ALT (> 5 times compared with the original)^xD * ^about		18% (5%)		14% (5%)		4% (2%)		19% (6%)
Increase ACT (> 5 times compared with the original)^x^* ^about		6%(1%)		4% (1 %)		2% (1 %)		4 % (0 %)
Skin and subcutaneous fatty tissue
Skin Reactions		1%(0%)		4% (4%)		19% (17%)		6% (8%)
Rash ^{^ o}		11% (3%)		20% (12%)		26% (20%)		27% (32 %)
Disorders from the musculoskeletal system
Hypertonus^about		2% (1%)		41% (31 %)		57% (57%)		26 % (24 %)
Myalgia * ^about		8% (8%)		23% (9 %)		19% (29%)		44% (28 %)
Myasthenia gravis		2% (2%)		39% (40 %)		57% (60%)		13% (10 %)
Backache		10% (7%)		26% (24%)		31% (32%)		36% (37%)
Pain in the extremities		6% (3%)		14% (12%)				0 % (0 %)
urinary system
Retention of urine		1%(1%)		4% (6%)		15% (13%)
Proteinuria (> 1+)^x		25% (26%)		14% (11%)		5% (5%)		5 % (3 %)
Increased urination		1%(1%)		6% (5%)		12% (11%)		3% (5%)
Urinary incontinence		1%(1%)		8% (15%)		20% (19%)		2% (1%)
Imperative urges		1%(1%)		8% (7%)		21% (17%)		4% (2 %)
Reproductive system
Dysmenorrhea		2% (0%)		<1% (<1%)		6% (5%)		18% (11 %)
Violation menstrual cycle *		1%(2%)		9% (13%)		10% (8%)		17% (8 %)
Metroragia		2% (0%)		12% (6%)		10% (10%)		15% (8 %)
Impotence		1%(0%)		7% (4%)		10% (11%)		2%(1%)
General reactions and reactions at the site of administration
Reactions at the site of administration (of various types) ^about§		52% (11%)		78% (20 %)		89% (37%)		85% (37 %)
Necrosis at the site of administration *^about		1%(0%)		5% (0 %)		6% (0%)		5% (0 %)
The flu-like syndrome & ^* ^about		44% (18%)		61% (40%)		43% (33%)		52 % (48 %)
Fever ^ * ^about		13% (5%)		40% (13 %)		29% (24%)		59 % (41 %)
Pain		4% (4%)		31% (25%)		59% (59%)		52 % (48 %)
Chest pain ^about		1%(0%)		5% (4%)		15% (8%)		15% (15%)
Peripheral edema		0% (0%)		7% (7%)		21% (18%)		7% (8%)
Asthenia *		22% (17%)		63% (58 %)		64% (58%)		49 % (35 %)
Chilliness * ^about		5%(1%)		23% (7 %)		22% (12%)		46 % (19 %)
Sweating *		2% (1 %)			6% (6%)		10% (10%)		23% (11 %)
Misery *		0%(1%)			8% (5 %)		6% (2%)		15 %(3 %)

laboratory deviation

It is reliably associated with interferon therapy with beta-lb in patients with ICU, p <0.05

* Reliably associated with interferon beta therapy-lb in patients with RRS, p <0.05

⁰ Reliably associated with interferon therapy with beta-lb in patients with VBDC, p <0.05

§ Reactions at the site of administration may include any adverse manifestations occurring at the injection site, for example: injection site bleeding, hypersensitivity, inflammation at the injection site, swelling at the injection site, necrosis at the injection site, pain at the injection site, edema at the site injections, and atrophy at the injection site; "Flu-like syndrome" refers to a combination of at least two of the following symptoms: fever, chills, myalgia, malaise, sweating.

Table 4. (the frequency is indicated in accordance with the categorization given: very often (> 10%), often (<10% - > 1%), infrequently (<1% - > 0.1%), rarely (<0.1% - > 0.01%) and very rarely (<0.01%)). Experience in the use of interferons beta-lb in patients with multiple sclerosis is limited, unwanted reactions that occur very rarely may not yet be detected (data are based on recorded spontaneous reports).

Class of organ system	Often > 1/10		Often >1/100 to <1/10	Infrequently >1 / 1,000 to <1/100	Rarely >1 / 10,000 to <1 / 1,000	Very rarely <0.01%
Blood and lymphatic system			Anemia	Thrombocytopenia	Bleeding * *
Immune system disorders					Anaphylactic ejections	Syndrome of increased capillary permeability in the presence of monoclonal gammopathy
Endocrine disorders			Hypothyroidism		Hyperthyroidism Pathology thyroid glands
Metabolic disorders			Weight gain Weight loss	Level up triglycerides of blood	Anorexia
Mental disorders			Confused Consciousness	Emotional lability Suicide attempts
Disturbances from the nervous system				Convulsions
Heart Disease			Tachycardia		Cardiomyopathy,
Vascular disorders				Hypertension	Decrease arterial pressure **
Disturbances from the respiratory system, thorax and mediastinum				Bronchospasm
Disorders from the gastrointestinal tract					Pancreatitis
Infringements from hepatobiliary tract		Increased blood bilirubin level		An increase in the level of gamma- glutamintranspecte andase hepatitis	Liver disorders, including hepatitis Liver failure
Skin and subcutaneous- fatty cellulose		Urticaria Itching Alopecia		Skin discoloration
Disturbances from the musculoskeletal system and connective tissue	Arthralgia
Disorders from the reproductive system and mammary glands		Menorrhagia
* frequency established in clinical trials ** Data of CJSC BIOCAD

Within each group, formed by the frequency of occurrence, the symptoms are presented in order of decreasing severity.

Overdose:Interferon beta-lb at doses up to 176 million IU intravenously three times a week in adult patients with malignant tumors did not cause serious adverse events.

Interaction:

Special studies of the interaction of interferon beta-lb with other drugs have not been conducted.

The effect of interferon beta-lb at a dose of 8 million IU a day on the metabolism of drugs in patients with multiple sclerosis is unknown. Against the background of the use of interferon beta-lb glucocorticosteroids and ACTE, prescribed for up to 28 days in the treatment of exacerbations, are well tolerated. The use of interferon beta-lb concomitantly with other immunomodulators (except for glucocorticosteroids or ACTH) has not been studied.

Interferons reduce the activity of microsomal hepatic enzymes of the cytochrome P450 system in humans and animals. Caution should be exercised in prescribing interferon beta-lb in combination with drugs that have a narrow therapeutic index, the clearance of which depends to a large extent on the activity of these enzymes (including antiepileptic drugs, antidepressants). It is also necessary to be careful when using any drugs that affect the hematopoiesis system at the same time.

There have been no studies on compatibility with antiepileptic drugs.

Special instructions:

Pathology of the immune system

The use of cytokines in patients with monoclonal gammapathy was sometimes accompanied by the development of a syndrome of systemic increase in the permeability of capillaries with shock-like symptoms and death.

Pathology of the gastrointestinal tract

In rare cases, against the background of the use of interferon beta-lb there was a development of pancreatitis, in most cases associated with the presence of hypertriglyceridemia.

The defeat of the nervous system

Patients should be informed that the side effect of interferon beta-lb there may be depression and suicidal thoughts, at the appearance of which you should immediately consult a doctor.

In two controlled clinical trials involving 1657 patients with a secondary progressive PC there were no significant differences in the incidence of depression and suicidal thoughts when using interferon beta-lb or placebo. Nevertheless, caution should be exercised in the administration of interferon beta-lb patients with depressive disorders and suicidal thoughts in the anamnesis.

If such phenomena occur on the background of treatment, consideration should be given to the feasibility of abolishing interferon beta-lb.

The preparation of interferon beta-lb it is necessary to use with caution in patients with cramps in the anamnesis,receiving therapy with antiepileptic drugs, especially if the seizures in these patients are not adequately controlled against the background of therapy with antiepileptic drugs.

Changes in laboratory indicators

Patients with thyroid dysfunction are recommended to check the function of the thyroid gland (thyroid hormones, thyroid-stimulating hormone) regularly, and in other cases - according to clinical indications.

In addition to standard laboratory tests administered in patients with multiple sclerosis, before starting therapy with interferon beta-lb, and also regularly during the period of treatment, it is recommended to perform a detailed blood test, including the determination of the leukocyte formula, and platelet counts and a biochemical blood test, and to check the liver function (for example, activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and g- glutamyl transferase (g-GT)).

When managing patients with anemia, thrombocytopenia, or leukopenia (individually or in combination), a more detailed monitoring of the expanded blood test may be required, including the determination of the number of red blood cells, leukocytes, platelets and the leukocyte formula.

Disturbances from the side of baked and bile ducts

Clinical studies have shown that interferon therapy with beta-lb often can lead to an asymptomatic increase in the activity of "liver" transaminases, which, in most cases, is slightly expressed and transient. As with the treatment with other interferons, beta-heavy liver damage (including liver failure) with the use of interferon beta-lb are rare. The most severe cases were observed in patients exposed to hepatotoxic drugs or substances, as well as in certain concomitant diseases (eg malignant tumors with metastasis, severe infections and sepsis, alcoholism).

When treatment with interferon beta-lb it is necessary to monitor liver function (including assessment of the clinical picture). Increased activity of transaminases in the serum requires careful monitoring and examination. With a significant increase in the activity of transaminases in the blood serum or the appearance of signs of liver damage (eg, jaundice), the drug should be discontinued.In the absence of clinical signs of liver damage or after the normalization of the activity of "liver" enzymes, it is possible to resume therapy with interferon beta-lb with observation of liver function.

Violation of the kidneys and urinary tract

Patients with severe renal failure should be prescribed

be careful.

Diseases of the cardiovascular system

The preparation of interferon beta-lb should be used with caution in patients with heart disease, in particular, with coronary heart disease, rhythm disorders and heart failure. The function of the cardiovascular system should be monitored, especially at the beginning of treatment.

There is no evidence in favor of a direct cardiotoxic effect of interferon beta-lb, However, associated with the use of interferon beta-lb influenza-like syndrome, can become a significant stress factor for patients with a significant cardiovascular pathology. During post-marketing surveillance, the cardiovascular system deteriorated very rarely in patients with a significant cardiovascular pathology,which was associated with the onset of treatment with interferon beta-lb.

There are rare reports of the occurrence of cardiomyopathy in the background of treatment with interferon beta-lb. With the development of cardiomyopathy, if it is supposed that this is due to the use of the drug, then treatment with interferon beta-lb should be discontinued.

General violations and violations at the injection site

Serious allergic reactions can occur (rare, but manifested in acute and severe form, such as bronchospasm, anaphylaxis and urticaria). In patients who received interferon beta-lb, There were cases of necrosis at the injection site (see "Side Effects" section). Necrosis can be extensive and spread to the muscular fascia, as well as adipose tissue and, as a result, lead to the formation of scars. In some cases, it is necessary to remove the necrotic areas or, more rarely, skin transplantation. The healing process can take up to 6 months.

If signs of damage to the integrity of the skin appear (for example, the flow of fluid from the injection site), the patient should consult a doctor before continuing injections of interferon beta-lb.

When multiple foci of necrosis appear, treatment with interferon beta-lb should be discontinued until the wound is completely healed. In the presence of a single focus, if necrosis is not too extensive, the use of interferon beta-lb can be continued, as in some patients, the healing of the necrotic area at the injection site occurred against the background of the use of interferon beta-1 preparationb.

To reduce the risk of developing a reaction and necrosis at the injection site, patients should be recommended:

- to carry out injections, strictly observing the rules of asepsis;

- each time to change the injection site;

- administer the drug strictly subcutaneously.

Periodically, one should monitor the correctness of the performance of independent

injections, especially when local reactions occur.

Immunogenicity

As in the treatment of any other drugs containing proteins, with the use of interferon beta-lb there is the possibility of the formation of antibodies. In a number of controlled clinical trials, serum analysis was performed every 3 months to detect the formation of antibodies to interferon beta-lb. In these studies, it was shown that neutralizing antibodies to interferon beta-lb developed in 23-41% of patients, which was confirmed by at least two subsequent positive results of laboratory tests. In 43-55% of these patients, in subsequent laboratory studies, a stable absence of antibodies to interferon beta-lb.

In a study involving patients with clinically isolated syndromes suggesting multiple sclerosis, the neutralizing activity, which was measured every 6 months, during appropriate visits was noted in 16.5-25.2% of patients receiving interferon beta-lb. Neutralizing activity was detected at least once in 30% (75) of patients receiving interferon beta-lb; in 23% (17) of them before the study was completed, the status of antibodies again became negative.

During the two-year study period, the development of neutralizing activity was not associated with a decrease in clinical efficacy (in terms of time to the onset of clinically significant multiple sclerosis).

It has not been proven that the presence of neutralizing antibodies has any significant effect on clinical outcomes. With the development of neutralizing activity, the appearance of any side reactions was not associated.

The decision to continue or discontinue therapy should be based on the indicators of the clinical activity of the disease, and not on the status of neutralizing activity.

Effect on the ability to drive transp. cf. and fur:Special studies have not been conducted. Undesirable effects from the CNS can affect the ability to drive and work with machinery. In this regard, care must be taken when dealing with potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions. If these side effects appear, you should refrain from performing these activities.

Form release / dosage:

Solution for subcutaneous administration, 8 million IU / mL, 8 million IU / 0.5 mL.

Packaging:

Solution for subcutaneous administration, 8 million IU / mL, 8 million IU / 0.5 mL.

1 ml (8 million IU / ml) into the bottles of colorless neutral glass I of the hydrolytic class, sealed with stoppers, with the rolling of aluminum caps. Each label is labeled.

5 bottles per circuit pack of PVC film. For 1, 2, 3 or 6 contour mesh packages with instructions for use are placed in a pack of cardboard.

0.5 ml (8 million IU / 0.5 ml) into three-component sterile syringes from colorless neutral glass I of the hydrolytic class. For each syringe stick a label. 1 syringe per contour mesh box made of PVC film.

For 1, 5 or 15 contour mesh packages with instructions for use are placed in a pack of cardboard.

A pack with bottles can be additionally completed: Completeness No. 1:

- disposable syringes with needles of 5, 10, 15 and 30 pcs, respectively;

- Needles for medical injection by 5, 10, 15 and 30 pcs, respectively;

- napkins alcoholic to 10, 20, 30 and 60 pcs, respectively. Completeness number 2:

- disposable syringes with needles of 5, 10, 15 and 30 pcs, respectively;

- needles of medical injection of two types of 5, 10, 15 and 30 pieces respectively;

- napkins alcoholic to 10, 20, 30 and 60 pcs, respectively. The pack with syringes can additionally be completed:

napkins alcoholic to 1, 5 and 15 pcs, respectively.

Storage conditions:

Store at a temperature of 2 to 8 ° C.

Within the indicated shelf life, an unopened vial / syringe can be stored by the patient for one month at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-007366/09

Date of registration:17.09.2009

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Information update date: & nbsp13.12.2015

Illustrated instructions

Instructions

Interferon beta-1b (Interferon beta-1b)