Benlist - instructions for use, dose, side effects, contraindications

Active substanceBelimumabBelimumab

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lyophilizate d / infusion

Dosage form: & nbsp

lyophilizate for the preparation of concentrate for the preparation of solution for infusions

Composition:

Name of components	Amount, mg
Name of components	400 mg	120 mg
Active substance
Belimumab	400.00 mg	120.00 mg
Excipients
Citric acid monohydrate	0.80 mg	0.24 mg
Sodium citrate dihydrate	13.50 mg	4.10 mg
Sucrose	400.00 mg	120.00 mg
Polysorbate 80	2.00 mg	0.60 mg

Description:

A whole, partially or completely crumbled lyophilized mass or lyophilized powder of white or almost white color.

Reconstituted solution: opalescent solution from colorless to light yellow color, free from visible particles.

Pharmacotherapeutic group:Immunosuppressive drugs

ATX: & nbsp

L.04.A Immunosuppressive drugs

Pharmacodynamics:Mechanism of action

Stimulator of B-lymphocytes (BLyS, also known as BAFF and TNFSF13), which belongs to the ligands of the family of tumor necrosis factor (TNF), suppresses apoptosis of B lymphocytes and stimulates the differentiation of B lymphocytes into plasma cells that produce immunoglobulins. Excessive expression is observed in patients with systemic lupus erythematosus (SLE) BLyS, which leads to an increase in the level of BLyS in the blood plasma.There is a strong correlation between the degree of activity of SLE (based on the national safety assessment of estrogens in lupus erythematosus (the Safety of Estrogen in Lupus Erythematosus National Assessment) - the index of activity of systemic lupus erythematosus [SELENA-SLEDAI]) and the level BLyS in the blood plasma. Belimumab is a fully human monoclonal antibody of the class IgGlX, which specifically binds to soluble BLyS and suppresses its biological activity. Belimumab binds to B-lymphocytes not directly, but due to binding to BLyS belimumab suppresses the viability of B-lymphocytes, including autoreactive clones, and reduces the differentiation of B-lymphocytes into plasma cells that produce immunoglobulins.

Pharmacodynamics

Decreased elevated serum levels IgG and antibodies to native (double-stranded) DNA (anti-dsDNA) was observed since the 8th week and lasted until the 52nd week of treatment. In patients with hypergammaglobulinemia before the study, who received belimumab and placebo, normalization of the level IgG by the 52nd week was observed in 49% and 20% of cases, respectively. In the group of belimumab among patients with the initial presence of anti-dsDNA a decrease in the number of patients with anti-dsDNA in comparison with the initial level; decrease in their number has become apparent since the 8th week, and by the 52nd week of anti-dsDNA have ceased to be defined in 16% of patients treated with belimumab and in 7% of patients receiving placebo. In patients with a low baseline complement level, treatment with belimumab was accompanied by an increase in the level of complement from the 4th week and throughout the subsequent time. By the 52nd week, the levels of complement components of C3 and C4 normalized in 38% and 44% of patients receiving belimumab, compared with 17% and 19% of patients receiving a placebo. The target of belimumab is BLyS. cytokine, critical for the survival of B-lymphocytes, their differentiation and proliferation. Belimumab significantly reduced the number of circulating B-lymphocytes, naïve and active forms, plasma cells and a subpopulation of lupus B-lymphocytes at the 52nd week. Reduction of the number of naive, plasma and short-lived plasma cells, as well as a subpopulation of lupus B-lymphocytes was observed starting from the 8th week.The number of memory cells initially increased, then slowly decreased to the baseline level by the 52nd week. Immunogenicity Two phase III studies in 4 patients out of 563 (0.7%) patients who received the drug at a dose of 10 mg / kg and in 27 of 559 (4.8%) patients who received the drug at a dose of 1 mg / kg, the formation of persistent antibodies to belimumab. The frequency of this phenomenon in the group of patients receiving belimumab in a dose of 10 mg / kg, may be lower due to a decrease in the sensitivity of the detection method in the presence of high concentrations of the drug. Neutralizing antibodies were detected in 3 patients who received belimumab in a dose of 1 mg / kg. However, the presence of antibodies to belimumab was relatively rare, therefore, because of the small number of patients with antibodies, no definite conclusions can be drawn regarding the effect of immunogenicity on the pharmacokinetics of belimumab.

Pharmacokinetics:Suction

Belimumab is administered as an intravenous infusion. The maximum concentration of belimumab in the blood serum was usually observed at the end of the infusion or shortly after its completion.Based on the results of modeling the curve of drug concentration versus time using typical values of the parameter in the population pharmacokinetic model, the maximum concentration in serum was 313 μg / ml.

Distribution

Belimumab was distributed in tissues with an insult to the volume of distribution equal to 5.29 liters.

Metabolism

Belimumab is a protein whose putative metabolism pathway consists of cleavage into small peptides and individual amino acids using widely distributed proteolytic enzymes. Classical studies of biotransformation of the drug were not conducted.

Excretion

The decrease in the concentration of belimumab in the serum was bi-exponential with a half-life of 1.75 days and a final half-life of 19.4 days. Systemic clearance was 215 ml / day.

Inter-drug interactions

Based on the results of population pharmacokinetic analysis, the concomitant use of mycophenolate mofetil, methotrexate, azathioprine and hydroxychloroquine does not significantly affect the pharmacokinetics of belimumab.A wide range of other drugs (non-steroidal anti-inflammatory drugs, acetylsalicylic acid, inhibitors of HMG-CoA reductase) also does not. The concomitant use of glucocorticosteroids and ACE inhibitors in conducting population pharmacokinetic analysis resulted in a statistically significant increase in systemic clearance. However, these effects were not clinically significant, since the magnitude of the deviations was within the natural variability of the clearance rates. Special groups of patients have a significant effect on the pharmacokinetics of belimumab.

Elderly patients

The use of belimumab was studied in a limited number of elderly patients. In the population pharmacokinetic analysis of the general population of patients with SLE who received the drug intravenously in the study, age had no effect on the exposure of belimumab. However, given the small number of patients aged 65 years and older, the influence of age can not be completely ruled out.

Children and teens

Information on the pharmacokinetics of the drug in patients of childhood is absent.

Patients with impaired renal function

Official studies to study the effect of renal failure on the pharmacokinetics of belimumab were not conducted. During the clinical trial belimumab was studied in a limited number of patients with SLE and renal insufficiency (creatinine clearance less than 60 ml / min, including a small number of patients with creatinine clearance less than 30 ml / min). Although proteinuria (at least 2 r/ day) led to an increase, and a decrease in creatinine clearance - to a decrease in clearance of belimumab, these changes were within the expected range of variability. Therefore, adjust the dose in patients with renal insufficiency is not recommended.

Patients with impaired hepatic function

Official studies to study the effect of hepatic insufficiency on the pharmacokinetics of belimumab were not conducted. Molecules IgGl, such as belimumab, are broken down by widespread proteolytic enzymes, which are present not only in liver tissue: therefore it is unlikely that a change in liver function will affect the removal of belimumab from the body.

Other characteristics of patients

Sex, race or ethnicity of patients did not have a significant effect on the pharmacokinetics of belimumab. The change in the action of belimumab, depending on the size of the body, is corrected by calculating the dose based on body weight.

Indications:

The use of Benlist is indicated to reduce the activity of the disease in adult patients receiving standard therapy with active systemic lupus erythematosus (SLE) and the presence of autoantibodies.

Contraindications:

Hypersensitivity to belimumab or one of the components of the drug; children's age till 18 years; pregnancy and lactation; active forms of infectious, immunodeficient and neoplastic diseases.

Carefully:

Severe active lupus erythematosus of the central nervous system, kidney; HIV infection; hypogammaglobulinemia (IgG <400 mg / ml); deficit IgA (IgA<10 mg / ml); transplantation of a large organ, hematopoietic stem cells, bone marrow or kidney (in anamnesis).

Simultaneous use with drugs aimed at inhibiting activity B-lymphocytes, and cyclophosphamide

Simultaneous use of belimumab with other drugs that specifically suppresses B-lymphocyte activity, or with intravenous cyclophosphamide has not been studied.Caution should be exercised with simultaneous treatment with belimumab and other drugs. directed at suppressing the activity of B-lymphocytes, or cyclophosphamide.

Risk of infection

As in the case of other immunomodulating agents, belimumab, in accordance with its
mechanism of action, can increase the potential risk of infection. It should be carefully monitored for patients who developed an infectious disease during treatment with belimumab. Doctors should be cautious in prescribing belimumab to patients with chronic infections. Patients receiving treatment for a chronic infection should not begin treatment with belimumab.
Risk of malignant tumors
As in the case of other muonomodulating agents, the mechanism of action of belimumab may increase the potential risk of developing malignant tumors. In clinical studies, there was no difference in the extent of malignant tumors in the groups treated with belimumab and in the placebo-treated groups.

Immunization

Do not vaccinate with live vaccines 30 days before or during treatment with belimumab, because the clinical safety of this combination has not been established.There are no data on secondary transmission of infection from persons who received vaccination to patients receiving belimumab. Due to the mechanism of its operation belimumab may violate the response to immunization. The effectiveness of vaccination in patients receiving belimumab, is unknown.
A few data suggest that belimumab has little effect on the ability to maintain a protective immune response in immunizations conducted prior to the appointment of belimumab.

Pregnancy and lactation:

Pregnancy

Data on the use of belimumab in pregnant women are limited; official research was not conducted. Antibodies to immunoglobulin G (IgG), including belimumab, can pass through the placental barrier. Belimumab should not be administered during pregnancy.

Women of childbearing age should follow measures to protect themselves from pregnancy during treatment with belimumab. During the use of belimumab and at least 4 months after the last administration of the drug, effective methods of contraception should be used.

In animal studies, there was no direct or indirect adverse effect of the drug on toxicity for the mother's body,the course of pregnancy or intrauterine development of the fetus. The changes associated with the administration of the drug in the young apes were limited to a reversible decrease in the number of B-lymphocytes.

Lactation

Data on the allocation of belimumab with milk in women or the absorption of belimumab into the systemic circulation from the intestine of the child after feeding are absent. Nevertheless, the presence of belimumab in breast milk of Javanese macaques was determined. Safety of use of belimumab during lactation is not established.

Dosing and Administration:The drug Benlista® is administered intravenously infusion.

Before administration, it must be reconstituted (dissolved) and diluted. The recommended dose is 10 mg / kg on treatment days 0, 14 and 28 and thereafter 1 time every 4 weeks. The drug should be used indefinitely. Infusion of belimumab should be performed within 1 hour. The drug should not be injected intravenously intravenously bolus or bolus. If a patient develops an infusion reaction, the rate of administration can be reduced or the drug may be suspended. Infusion should be discontinued immediately if the patient develops a life-threatening undesirable reaction.Infusion should be performed under the careful supervision of medical personnel and prepare the weight necessary to prevent hypersensitivity reactions, including anaphylactic shock. Patients should be monitored during and after administration of belimumab during the appropriate period. Before the infusion of belimumab, premedication can be performed with the use of H1-histamine receptor blockers in combination with or without antipyretic agents.

The drug Benlista® does not contain preservatives, so the reconstitution (dissolution) and subsequent dilution of the drug should be carried out under aseptic conditions. It is necessary to allow the vial to warm to room temperature within 10-15 minutes. 120 mg of belimumum in a single-use vial should be dissolved in 1.5 ml of sterile water for injection to reach a final concentration of 80 mg / ml of belimumab. 400 mg of belimumum in a single-use vial should be dissolved in 4.8 ml of sterile water for injection to reach a final concentration of 80 mg / ml of belimumab. To reduce the formation of foam, a jet of water for injection should be directed to the wall of the bottle.The contents of the vial at room temperature should be gently stirred in a circular motion for 60 seconds. After this, the bottle should be left to stand on the table for 5 minutes, and then again mix the contents of the bottle for 60 seconds and leave it to stand for 5 minutes. The described procedures of stirring and settling the contents of the vial are repeated until the lyophilizate dissolves completely. Do not shake the bottle. The dissolution process usually takes 10 minutes to 15 minutes after the addition of sterile water, but it can last up to 30 minutes. Protect the resulting solution from direct sunlight. If a mechanical device is used to dissolve belimumum, the speed of rotation should not exceed 500 rpm, and the vial rotation time should not exceed 30 minutes.

The reconstituted solution must be opalescent from colorless to light yellow, free of visible particles. However, the presence of small air bubbles in the solution is expected and permissible. The resulting solution is diluted to 250 ml with 0.9% sodium chloride solution for intravenous infusion. A 5% dextrose solution for intravenous administration is incompatible with belimumab and should therefore not be used.From an infusion tank containing 250 ml of 0.9% sodium chloride solution, remove and dispose of a volume equal to the volume of the solution of belimumum required to administer the dose of the drug calculated for the patient. Then add the required volume of the reconstituted belimumab solution to this infusion container. Gently invert the container to mix the solution. Remains of unused solution of belimumab in vials should be disposed of. Before use, visually check the presence of undissolved particles in the solution and discoloration. Dispose of the solution if undissolved particles are found in it or a discoloration of the solution is observed. If the solution is not used immediately. it should be protected from direct sunlight and stored in a refrigerator at a temperature of 2 ° C to 8 ° C. The drug diluted in saline solution of sodium chloride can be stored for no more than 8 hours at a temperature of 2 ° C to 8 ° C or at room temperature. The total time from the preparation of the reconstituted solution to the completion of the infusion should not exceed 8 hours.

Special patient groups

Children

The use of belimumab in patients under the age of 18 years has not been studied. Data on the safety and efficacy of belimumab in patients of this age group are not available.

Elderly patients

Despite. that there are limited data on the use of the drug in elderly patients, dose adjustment is not recommended.

Patients with impaired renal function

Official studies of the use of belimumab for the treatment of patients with systemic lupus erythematosus with renal insufficiency have not been conducted. The study of the action of belimumab was carried out in a limited number of patients with SLE and renal insufficiency. Dose correction in the treatment of patients with renal insufficiency is not required.

Patients with impaired hepatic function

Official studies of the use of belimumab for the treatment of patients with systemic lupus erythematosus with hepatic insufficiency have not been conducted. However, according to the results of clinical studies, the functional state of the liver did not have a significant effect on the pharmacokinetics of belimumab. Given these results, and also the fact that, in general, the liver does not directly participate in antibody clearance,it can be considered that there is practically no need for dose adjustment in persons with hepatic insufficiency.

Side effects:The adverse events presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1/10 000 and < 1/1 000), very rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug.

Frequency of occurrence of undesirable phenomena

Immune system disorders

Often: hypersensitivity reaction *. Infrequently: anaphylactic reaction. angioedema.

Disorders from the rut and subcutaneous tissues

Infrequent: rash, hives.

General disorders and disorders at the site of administration

Often: fever. infusion reactions *, urticaria.

Infections and parasitic diseases

Very often: infections (not opportunistic).

* "Hypersensitivity reactions" include a whole group of terms, including anaphylaxis, and can manifest as arterial hypotension, Quincke edema, urticaria, or other: rash, itching, dyspnea."Infusion reactions" encompass a whole group of terms and can manifest as bradycardia, myalgia, headache, rash, urticaria, fever, arterial hypo- or hypertension, dizziness, and joint pain. In connection with the overlap of signs and symptoms in each case, it is not possible to distinguish between hypersensitivity reactions and infusion reactions.

In 0.4% of patients, clinically significant hypersensitivity reactions associated with the administration of belimumab and requiring complete discontinuation of the drug were recorded. As a rule, such reactions were observed on the day of infusion, and patients with a history of several episodes of drug allergy or severe hypersensitivity may be at increased risk. There was a delay in the onset of an acute hypersensitivity reaction for several hours after the infusion and a repetition of clinically significant reactions after resolving the symptoms of the primary reaction against the background of appropriate treatment. There were also hypersensitivity reactions of delayed type (mild), manifested by such symptoms as rash, nausea, fatigue, myalgia, headache and face swelling.

Infections

In clinical trials, the overall incidence of infections was 70% in the group receiving belimumab, and 67% in the placebo group. Infections occurring in at least 3% of patients taking belimumab, and at least 1% more often than patients taking placebo, were as follows: nasopharyngitis. bronchitis, pharyngitis, cystitis, viral gastroenteritis. Serious infections occurred in 5% of patients who received belimumab or placebo.

Overdose:

In clinical practice, cases of overdose of belimumab were not observed. In patients who received two doses of the drug at 20 mg / kg body weight as intravenous infusions at 21 days intervals, there was no increase in the incidence or severity of adverse reactions compared to patients receiving the drug at doses of 1, 4 or 10 mg / kg body weight .

Interaction:

Studies of the inter-drug interactions of belimumab with other drugs have not been conducted.

In clinical trials in patients with SLE, simultaneous administration of mycophenolate mofetil, azathioprine, hydroxychloroquine, methotrexate, nonsteroidal anti-inflammatory drugs,Acetylsalicylic acid and inhibitors of HMG-CoA reductase did not significantly affect the action of belimumab.

The drug is incompatible with dextrose.

Special instructions:

Infusion reactions and hypersensitivity reactions

The introduction of belimumab can lead to the development of reactions associated with the infusion administration of the drug, and hypersensitivity reactions, which can be severe and fatal. In case of severe reaction, the introduction of belimumab should be interrupted and appropriate medication should be prescribed. Patients who have a history of several cases of drug allergy or severe hypersensitivity may be at increased risk. Before the infusion of belimumab, premedication can be performed with the use of H1-histamine receptor blockers in combination with or without antipyretic agents. To assess whether premedication reduces the frequency and severity of the infarction, data is insufficient. According to clinical studies, serious reactions associated with the infusion of the drug,and severe hypersensitivity reactions developed in less than 1% of patients, and included anaphylactic reaction, bradycardia, hypotension, angioedema and dyspnea. Infusion reactions developed more often during the first two infusions, with each subsequent infusion, there was a tendency to decrease the number of reactions. As there were episodes of a delayed onset of an acute hypersensitivity reaction. patients should be monitored during and after administration of belimumab during the appropriate period. Patients receiving belimumab, should be aware of the potential danger, subjective and objective symptoms of such reactions, as well as the need to seek immediate medical help. There were also hypersensitivity reactions of delayed type (mild), manifested by such symptoms as rash, nausea, fatigue, myalgia, headache and face swelling.

Progressive multifocal leukoencephalopathy. There have been reports of the development of progressive multifocal leukoencephalopathy (PML), which led to neurologic deficits,including those with a fatal outcome, in patients with SLE receiving immunosuppressive therapy, including belimumab. The presence of PML should be excluded in any patient with newly developed or progressing neurologic complaints and objective symptoms. The patient should be examined by a neurologist or other appropriate specialist and, in the case of confirmation of the diagnosis of PML, consideration should be given to the abolition of the immunosuppressive therapy, including belimumab.

Effect on the ability to drive transp. cf. and fur:

Studies of the influence of belimumab on the ability to drive a car or control mechanical means were not conducted. Pharmacological characteristics of belimumab suggest that it does not adversely affect the ability to carry out such activities.

When considering the ability of the patient to perform tasks that require increased concentration, complex motor and cognitive skills, the patient's clinical condition and the safety profile of belimumab should be taken into account.

Form release / dosage:

Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions, 120 mg, 400 mg.

Packaging:For 120 mg of belimumab or 400 mg of belimumab in a bottle of clear, colorless glass (type I, Hept. F.), sealed with a stopper of chlorobutyl rubber and coated with an aluminum cap. 1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of 2 to 8 ° C. Do not freeze. Keep in original packaging until use.

Keep out of the reach of children.

Transport at a temperature of 2 to 8 ° C, protecting from light. Do not freeze.

Shelf life:

5 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001557

Date of registration:02.03.2012 / 03.10.2016

Expiration Date:02.03.2017

The owner of the registration certificate: GlaxoSmithKline SpA GlaxoSmithKline SpA Italy

Manufacturer: & nbsp

GlaxoSmithKline Manufacturing, S.p.A. Italy

Representation: & nbspGlaxoSmithKline group of companies GlaxoSmithKline group of companies Unknown

Information update date: & nbsp23.01.2017

Illustrated instructions

Instructions

Benlist® (Benlista®)