Benlista

General characteristics. Structure:

Lyophilisate for preparation of a concentrate for preparation of solution for infusions in the form of integral, partially or completely crumbed lyophilized mass or the lyophilized powder of white or almost white color; the recovered solution - opalescent solution from colourless till light yellow color, free from visible particles.

Active ingredient: белимумаб 400 mg

Excipients: citric acid monohydrate of 0.8 mg, citrate sodium dihydrate of 13.5 mg, sucrose of 400 mg, mg polysorbate 80 2.

Lyophilisate for preparation of a concentrate for preparation of solution for infusions in the form of integral, partially or completely crumbed lyophilized mass or the lyophilized powder of white or almost white color; the recovered solution - opalescent solution from colourless till light yellow color, free from visible particles.

Active ingredient: белимумаб 120 mg

Excipients: citric acid monohydrate of 0.24 mg, citrate sodium dihydrate of 4.1 mg, sucrose of 120 mg, polysorbate of 80 0.6 mg.

Pharmacological properties:

Action mechanism

The stimulator of V-lymphocytes (BLyS, is also known as BAFF and TNFSF13) relating to ligands of family of the tumor necrosis factor (TNF) suppresses apoptosis of V-lymphocytes and stimulates a differentiation of V-lymphocytes in the plasmocytes producing immunoglobulin. At patients with the system lupus erythematosus (SLE) the excess expression of BLyS is observed. There is a strong correlation communication between a hard currency degree of activity (on the basis of national assessment of safety of estrogen at a lupus erythematosus (the Safety of Estrogen in Lupus Erythematosus National Assessment) — an index of activity of a system lupus erythematosus [SELENA-SLEDAI]) and the BLyS level in a blood plasma.

Belimumab is completely human monoclone of the class IgGλ which specifically contacts soluble BLyS of the person and suppresses his biological activity. Belimumab contacts V-lymphocytes not directly, but due to linkng with BLyS белимумаб suppresses viability of V-lymphocytes, including autoreactive clones, and reduces a differentiation of V-lymphocytes in the plasmocytes producing immunoglobulin.

Pharmacodynamics

Decrease in the increased serumal IgG levels and antibodies to two-chained DNA (anti-dsDNA) was observed, since 8th week, and continued till 52nd week of treatment. At patients with a hypergammaglobulinemia is prior to the research, receiving белимумаб and placebo, normalization of the gG level by 52nd week was observed in 49% and 20% of cases respectively. In group of a belimumab among patients with initial existence of anti-dsDNA reduction of number of patients with anti-dsDNA in comparison with initial level was observed; decrease in their quantity became obvious since 8th week, and by 52nd week of anti-dsDNA ceased to be defined at 16% of the patients receiving treatment belimumaby and at 7% of the patients receiving placebo.

At patients with the low initial level of a complement therapy by drug Benlista was followed by increase in its level, since 4th week, and throughout all subsequent time. By 52nd week the SZ and S4 levels were normalized respectively at 38% and 44% of the patients receiving белимумаб in comparison with 17% and 19% of the patients receiving placebo.

Target of a belimumab is BLyS, cytokine crucial for survival of V-lymphocytes, their differentiation and proliferation. Belimumab considerably reduced quantity of the circulating V-lymphocytes, native and active forms, plasmocytes and subpopulation of lupoid V-lymphocytes on the 52nd week. Decrease in quantity of untrained forms, plasmatic and short-lived plasmocytes, and also subpopulations of lupoid V-lymphocytes was observed since 8th week. The number of memory cells originally increased, then slowly decreased to initial level by 52nd week.

Immunogenicity

In two researches of a phase III at 4 of 563 (0.7%) the patients receiving drug in a dose of 10 mg/kg and at 27 of 559 (4.8%) the patients receiving drug in a dose of 1 mg/kg formation of persistent antibodies to a belimumab was observed. Frequency of this phenomenon in group of the patients receiving a dose of 10 mg/kg can be lower owing to reduction of sensitivity of a technique of definition in the presence of high concentration of drug. Neutralized antibodies were found in 3 patients receiving белимумаб in a dose of 1 mg/kg. However antibody formation to a belimumab met rather seldom therefore owing to small number of patients with existence of antibodies any certain conclusions concerning influence of an immunogenicity on pharmacokinetics of a belimumab cannot be drawn.

Pharmacokinetics. Absorption

Belimumab is entered in a look into infusions. Cmax of a belimumab in blood serum was, as a rule, observed at the end of infusion or soon after its end. By results of modeling of curve dependence of concentration of drug from time with use of typical values of parameter in the population pharmacokinetic Cmax model in blood serum made 313 mkg/ml.

Distribution

Belimumab was distributed in fabrics with the general Vd equal of 5.29 l.

Metabolism

Belimumab is protein which estimated way of metabolism consists in splitting on small peptides and separate amino acids by means of eurysynusic proteolytic enzymes. Classical researches of biotransformation of drug were not conducted.

Removal

Decrease in concentration of a belimumab in serum had bieksponentsialny character with the semi-distribution period 1.75 days and with final T1/2, equal 19.4 days. The system clearance made 215 ml /

Intermedicinal interactions

The accompanying use of a mikofenolat of a mofetil, Azathioprinum and hydroxychloroquine does not exert considerable impact on pharmacokinetics of a belimumab what results of the population pharmacokinetic analysis testify to. Broad range of other medicines (NPVS, acetylsalicylic acid, HMG-CoA reductase inhibitors) has also no significant effect on pharmacokinetics of a belimumab. The accompanying introduction of steroids and APF inhibitors when carrying out the population pharmacokinetic analysis led to statistically significant increase in system clearance. However these effects had no clinical value as the size of deviations was in limits of natural variability of indicators of clearance.

Pharmacokinetics in special clinical cases Patients of advanced age

Use of a belimumab was studied at the limited number of elderly patients. In the population pharmacokinetic analysis of the general population of patients from the hard currencies receiving drug in/in within the researches, the age did not exert impact on exposure of a belimumab. However, considering the small number of patients at the age of 65 years is also more senior, influence of age cannot be finally excluded.

Children and teenagers

Information on drug pharmacokinetics at patients of children's age is absent.

Patients with a renal failure

Official researches on studying of influence of a renal failure on pharmacokinetics of a belimumab were not conducted. During clinical tests белимумаб it was studied at limited number of patients with hard currency and a renal failure (clearance of creatinine/KK/<60 ml/min., including a small number of patients with KK <30 ml/min.). Though the proteinuria (> 2 g/) led to increase, and reduction of KK — to decrease in clearance of a belimumab, these changes were in limits of the expected variability range. Therefore, correction of a dose with a renal failure is not required from patients.

Patients with an abnormal liver function

The official researches devoted to studying of influence of a liver failure on pharmacokinetics of a belimumab were not conducted. The molecules IgG, such as белимумаб, are split by eurysynusic proteolytic enzymes which are present not only at hepatic fabric; therefore change of function of a liver, most likely, does not exert impact on removal of a belimumab from an organism.

Other characteristics of patients

Floor, racial or ethnic origin of patients had no significant effect on pharmacokinetics of a belimumab. Change of action of a belshchmumab depending on the sizes of a body korrigirutsya by means of calculation of a dose on the basis of body weight.

Indications to use:

— for decrease of the activity of a disease at the adult patients receiving standard therapy with the active system lupus erythematosus (SLE) and existence of autoantibodies.

Route of administration and doses:

The recommended dose makes 10 mg/kg in days of treatment 0, 14 and 28 and further 1 time each 4 weeks. The drug should be administered vaguely long.

Infusion of a belimumab has to be performed within 1 hour. Benlist's drug should not be administered in/in struyno.

At emergence at the patient of infusional reactions rate of administering can be reduced or administration of drug can be suspended. Infusion should be interrupted immediately if at the patient life-threatening undesirable reaction develops.

Before infusion of a belimumab premedication using blockers histamine H1 receptors together with use of an antipyretic or without it can be carried out.

Benlist's drug is administered in/in kapelno, before introduction it needs to be recovered (to dissolve) and part.

Benlist's drug does not contain preservatives therefore dissolution and the subsequent cultivation of drug has to be carried out in aseptic conditions. Let's a bottle heat up to room temperature within 10-15 min. 120 mg of a belimumab in a bottle for single use it is necessary to dissolve in 1.5 ml of sterile water for injections for achievement of final concentration of a belimumab 80 mg/ml. 400 mg of a belimumab in a bottle for single use need to be dissolved in 4.8 ml of sterile water for injections for achievement of final concentration of a belimumab 80 mg/ml.

The water stream for injections needs to be directed to a bottle wall for the maximum reduction of foaming. Bottle contents in the conditions of room temperature should be mixed accurately roundabouts during 60 sec. After that it is necessary to leave a bottle to stand on a table within 5 min., and then it is necessary to mix bottle contents again during 60 sec. and to leave it to stand within 5 min. The described procedures of hashing and upholding of contents of a bottle are repeated until lyophilisate is not dissolved completely. Do not stir up a bottle.

Dissolution process usually takes from 10 to 15 min. after addition of sterile water, but it can last up to 30 min. Protect the received solution from a sunlight.

If for dissolution of a belimumab the mechanical device is used, the speed of rotation should not exceed 500 rpm, and time of rotation of a bottle should not exceed 30 min.

The recovered solution has to be opalescent from colourless till light yellow color, free from visible particles. However presence at solution of small vials of air is allowed.

The received solution gets divorced to 250 ml of 0.9% normal saline solution of sodium of chloride for in/in infusions.

5% dextrose solution for in/in introductions with belimumaby is incompatible and therefore it should not be used.

From the infusional capacity containing 250 ml of normal saline solution of sodium of chloride take the volume equal to the volume of solution of the belimumab which is required for introduction of the dose of drug calculated for this patient. Then add the necessary volume of the received solution of a belimumab to this capacity for infusions. Accurately turn capacity to mix solution. The remains of unused solution of a belimumab in bottles have to be utilized.

Before use visually check existence in solution of not dissolved particles and coloring change. Utilize solution if at it there are not dissolved particles or solution coloring change is observed.

If solution of drug is not used at once, it has to be protected from direct sunshine and be stored in the refrigerator at a temperature from 2 °C to 8 °C. The drug divorced in normal saline solution of sodium of chloride can be stored no more than 8 h at a temperature from 2 °C to 8 °C or at the room temperature.

Special groups of patients

Use of a belimumab for patients is younger than 18 years was not studied. Data on safety and efficiency of a belimumab at patients of this age group are absent.

In spite of the fact that data on use of drug for elderly patients are limited, it is not recommended to carry out dose adjustment.

Official researches of use of a belimumab for treatment of patients with a system lupus erythematosus with a renal failure were not conducted. Studying of action of a belimumab was carried out at limited number of patients with hard currency and the phenomena of a renal failure. Dose adjustment at treatment of patients with a renal failure is not required.

Official researches of use of a belimumab for treatment of patients with a system lupus erythematosus with a liver failure were not conducted. However, according to results of clinical trials, the functional condition of a liver did not exert significant impact on pharmacokinetics of a belimumab. Considering these results, and also that fact that, in general, the liver directly does not participate in clearance of antibodies, it is possible to consider that need for dose adjustment at persons with a liver failure is practically absent.

Features of use:

Infusional reactions and reactions of hypersensitivity

Introduction of a belimumab can lead to development of the reactions connected with administration of drug, and hypersensitivity reactions. In case of development of heavy reaction introduction of a belimumab it is necessary to interrupt and appoint the corresponding medicamentous therapy.

Before infusion of a belimumab premedication using blockers histamine H1 receptors together with use of an antipyretic or without it can be carried out.

According to clinical trials, the serious reactions connected with administration of drug and reactions of hypersensitivity developed less than at 1% of patients and included anaphylactic reactions, bradycardia, hypotension, a Quincke's disease and an asthma. Infusional reactions developed in time of performing the first two infusions more often, with each subsequent infusion the tendency to reduction of number of reactions was noted.

Influence on ability to driving of motor transport and to control of mechanisms

Researches of influence of a belimumab on ability of driving of the car or management of mechanical means were not conducted. Pharmacological characteristics of a belimumab give the grounds to consider that it does not exert negative impact on ability to carry out such types of activity.

Side effects:

The undesirable phenomena given below are listed depending on anatomo-physiological classification and frequency of occurrence. Frequency of occurrence is defined as follows: very often (> 1/10), it is frequent (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), is rare (> 1/10 000 and <1/1000), is very rare (<1/10 000, including separate cases). Categories of frequency were created on the basis of clinical trials of drug.

From immune system: often - hypersensitivity reaction; infrequently - anaphylactic reaction, a Quincke's disease.

From skin and a hypodermic fatty tissue: often - rash.

The general reactions and reactions in an injection site: often - fever, infusional reactions, a small tortoiseshell.

Also at patients the following undesirable phenomena were noted: nausea, diarrhea, hyperthermia, infections, bronchitis, cystitis, nasopharyngitis, pharyngitis, depression, sleeplessness, migraine, leukopenia, extremity pain. Relationship of cause and effect of these undesirable phenomena using drug is not established.

At 0.4% of patients clinically significant reactions of hypersensitivity connected with introduction of a belimumab and which demanded full drug withdrawal were registered. As a rule, such reactions were observed during the first infusions.

Interaction with other medicines:

Researches of intermedicinal interactions of a belimumab with other drugs were not conducted.

In clinical tests at patients with hard currency co-administration of a mikofenolat of a mofetil, Azathioprinum, hydroxychloroquine, a methotrexate, NPVS, acetylsalicylic acid and inhibitors of HMG-CoA reductase had no significant effect on action of a belimumab.

Drug is incompatible with a dextrose.

Contraindications:

— hypersensitivity to a belimumab or one of drug components;

— children's age up to 18 years;

— pregnancy;

— lactation period;

— active forms of infectious, immunodeficient and tumoral diseases.

With care: crushing active lupoid defeat of TsNS, kidneys; HIV infection; hypogammaglobulinemia (IgG <400 mg/ml); deficit IgA (IgA <10 mg/ml); change of large body, haematopoietic stem cells, marrow or kidneys (in the anamnesis).

Simultaneous use of a belimumab with other drugs directionally suppressing activity of V-lymphocytes or with in/in cyclophosphamide was not studied. It is necessary to be careful at simultaneous treatment belimumaby and other drugs directed to suppression of activity of V-lymphocytes or cyclophosphamide.

As well as in cases with other immunomodulators, the mechanism of action of a belimumab can increase potential risk of development of infections. It is necessary to watch patients at whom during treatment belimumaby the infectious disease developed carefully. Doctors should show care at purpose of a belimumab to patients with persistent infections. The patients receiving treatment concerning persistent infection should not begin therapy belimumaby.

As well as in cases with other immunomodulators, the mechanism of action of a belimumab can increase potential risk of development of malignant tumors. In clinical trials distinction in degree of malignant tumors in the groups receiving treatment belimumaby and the groups receiving placebo was not noted.

It is not necessary to carry out vaccination by live vaccines in 30 days prior to or during treatment belimumaby as clinical safety of such combination was not established. There are no data on secondary transmission of infection from the persons who received vaccination, to the patients receiving белимумаб. Owing to the mechanism of the action белимумаб can violate the response to immunization. Efficiency of vaccination at the patients receiving белимумаб is unknown. Not numerous data allow to assume what белимумаб exerts insignificant impact on ability to support a protective immune response at the immunization which is carried out before purpose of a belimumab.

 

Use of drug BENLISTA at pregnancy and feeding by a breast

Data on use of a belimumab at pregnant women are limited; official researches were not conducted. Antibodies to G(IgG) immunoglobulin, including белимумаб, can pass through a placental barrier. Belimumab it is not necessary to appoint during pregnancy.

Women of childbearing age should observe measures for protection from pregnancy during treatment belimumaby. During use of a belimumab and at least within 4 months after the last administration of drug it is necessary to use effective methods of contraception.

In researches on animals the direct or mediated harmful effects of drug concerning toxicity for an organism of mother, the course of pregnancy or pre-natal fetation were not revealed. The changes in an organism of cubs of monkeys connected with administration of drug were limited to reversible decrease in number of V-lymphocytes.

The allocations of a belimumab given relatively with milk at women or absorption of a belimumab in a system blood stream from the child's intestines after feeding are absent. Nevertheless, existence of a belimumab in breast milk of the Javanese macaques was defined. Safety of use of a belimumab during a lactation is not established.

Use at abnormal liver functions
Official researches of use of a belimumab for lecheniyapatsiyent with a system lupus erythematosus with a liver failure were not conducted. However according to results of clinical trials the functional condition of a liver did not exert significant impact on pharmacokinetics of a belimumab. Considering these results, and also that fact that, in general, the liver directly does not participate in clearance of antibodies, it is possible to consider that need for dose adjustment at persons with a liver failure is practically absent.

Use at renal failures
Official researches of use of a belimumab for treatment of patients with a system lupus erythematosus with a renal failure were not conducted. Studying of action of a belimumab was carried out at limited number of patients with hard currency and the phenomena of a renal failure. Dose adjustment at treatment of patients with a renal failure is not required.

Use for elderly patients
In spite of the fact that data on use of drug for elderly patients are limited, it is not recommended to carry out dose adjustment.

Use for children

Use of a belimumab for patients is younger than 18 years was not studied. Data on safety and efficiency of a belimumab at patients of this age group are absent.

Overdose:

In clinical practice of cases of overdose of a belimumab it was not observed. At the patients receiving two doses of drug on 20 mg/kg of body weight in a look in/in infusions at an interval of 21 days increase in frequency or weight of undesirable reactions in comparison with the patients receiving drug in doses of 1, 4 or 10 mg/kg of body weight was not observed.

Storage conditions:

Drug should be stored in protected from light, the place, unavailable to children, at a temperature from 2 to 8 °C; not to freeze. To store in original packaging until use. To transport at a temperature from 2 to 8 °C, protecting from light; not to freeze. A period of validity - 3 years. Not to apply after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

400 mg - bottles glass (1) - packs cardboard.

120 mg - bottles glass (1) - packs cardboard.