Universal reference book for medicines
Product name: BENLISTA ® (BENLYSTA ® )

Active substance: belimumab

Type: Immunosuppressive drug

Manufacturer: GlaxoSmithKline Trading (Russia) manufactured by GlaxoSmithKline Manufacturing (Italy)
Composition, form of production and packaging
Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions
in the form of 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.
1 f.

belimumab 120 mg

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

Glass bottles (1) - cardboard packs.

Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions in the form of 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.
1 f.

belimumab 400 mg

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

Glass bottles (1) - cardboard packs.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

Mechanism of action

The B-lymphocyte stimulant (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 immunoglobulin.
Excess expression of BLyS is observed in patients with systemic lupus erythematosus (SLE). There is a strong correlation between the degree of activity of SLE (based on the National Safety Assessment of Estrogens in Lupus Erythematosus National Assessment - the index of activity of systemic lupus erythematosus [SELENA-SLEDAI]) and the level of BLyS in blood plasma.
Belimumab is a completely human monoclonal antibody of class IgG 1?
, which specifically binds to soluble human BLyS and suppresses its biological activity.Belimumab binds to B-lymphocytes indirectly, but due to binding to BLyS, belimumab suppresses the viability of B-lymphocytes, incl. autoreactive clones, and reduces the differentiation of B-lymphocytes into plasma cells that produce immunoglobulins.
Pharmacodynamics

Reduction of elevated serum levels of IgG and antibodies to native (double-stranded) DNA (anti-dsDNA) was observed starting from week 8, and lasted until the 52nd week of treatment.
In patients with hypergammaglobulinemia prior to initiating the study, receiving belimumab and placebo, the normalization of the IgG level 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 was observed compared to baseline; the decrease in their number became evident starting from the 8th week, and by the 52nd week, anti-dsDNA ceased to be detected in 16% of patients treated with belimumab and in 7% of patients receiving placebo.
In patients with a low baseline complement level, therapy with Benlist® was accompanied by an increase in its level, beginning with the 4th week, and throughout the subsequent time.
By week 52, the levels of C3 and C4 normalized respectively in 38% and 44% of patients receiving belimumab, compared with 17% and 19% of patients receiving placebo.
The target of belimumab is BLyS, a cytokine that is critical for the survival of B lymphocytes, their differentiation and proliferation.
Belimumab significantly reduced the number of circulating B-lymphocytes, native 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.
In a long-term, uncontrolled, extended study, the number of B lymphocytes (including naïve and active forms, plasma cells and a subpopulation of lupus B lymphocytes) and IgG concentration were observed for more than 7 years of therapy.
After more than 7 years of treatment, a significant and steady decrease in the number of B lymphocytes in different subpopulations was observed, the median decrease was 87% for naive B lymphocytes, 67% for B memory cells, 99% for activated B lymphocytes and 92% for plasma cells. Approximately after 7 years, the median decrease in IgG concentration was 28% and was observed in 1.6% of patients with a decrease in IgG concentration below 400 mg / dL. During the course of the study, the described frequency of occurrence of undesired reactions as a whole remained unchanged or decreased.
Immunogenicity

Two studies of phase III of belimumab for IV administration in 4 of 563 (0.7%) patients receiving the drug at a dose of 10 mg / kg and 27 of 559 (4.8%) patients receiving the drug at a dose of 1 mg / kg, the formation of persistent antibodies to belimumab.
The frequency of reporting this phenomenon in the group of patients receiving belimumab at a dose of 10 mg / kg may be lower than the actual frequency due to a decrease in the sensitivity of the detection technique in the presence of high concentrations of the drug.
Neutralizing antibodies were detected in 3 patients who received belimumab IV at a dose of 1 mg / kg.
However, the presence of antibodies to belimumab in patients treated with belimumab w / v was relatively infrequent, therefore, due to the small number of patients with antibodies, no definite conclusions can be drawn regarding the effect of immunogenicity on the pharmacokinetics of belimumab.
PHARMACOKINETICS

The pharmacokinetic parameters presented below are based on population-based calculation parameters for 563 patients who received belimumab intravenously at a dose of 10 mg / kg in two Phase III clinical trials.

Suction

With intravenous administration of C max, belimumab in serum was usually observed at the end of the infusion or shortly after it was complete.
Based on the results of modeling the curve of drug concentration versus time using typical values ​​of the parameter in the population pharmacokinetic model, C max in serum was 313 μg / ml.
Distribution

Belimumab was distributed in tissues with a total V d ,
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

With IV introduction, a decrease in the concentration of belimumab in the serum was bi-exponential with a half-life of 1.75 days and a final T 1/2 of 19.4 days.Systemic clearance was 215 ml / day.

Inter-drug interactions

The concomitant use of mycophenolate mofetil, azathioprine, methotrexate and hydroxychloroquine does not significantly affect the pharmacokinetics of belimumab with intravenous administration, as evidenced by the results of population pharmacokinetic analysis.
A wide range of other drugs (NSAIDs, acetylsalicylic acid, HMG-CoA reductase inhibitors) also does not have a significant effect on the pharmacokinetics of belimumab. The concomitant use of GCS and ACE inhibitors in conducting population pharmacokinetic analysis with intravenous administration resulted in a statistically significant increase in systemic clearance. However, the effects of GCS and ACE inhibitors with iv administration of belimumab were not clinically significant, the magnitude of the deviation was within the limits of the natural variability of the clearance rates.
Pharmacokinetics in special clinical cases

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 IV 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 clinical trials, belimumab for intravenous administration was studied in a limited number of patients with SLE and renal insufficiency (CC <60 mL / min, including a small number of patients with QC <30 mL / min). With IV injection of proteinuria (at least 2 g / day) led to an increase in clearance of belimumab, and a decrease in CK - to a decrease in clearance of belimumab. These changes were within the expected range of variability for IV introduction. Consequently, dose adjustment in patients with renal insufficiency is not required.
Patients with impaired hepatic function

Official studies devoted to the study of the effect of hepatic insufficiency on the pharmacokinetics of belimumab were not conducted.
IgG 1 molecules, such as belimumab, are cleaved by widespread proteolytic enzymes, which are present not only in the hepatic tissue; so it is unlikely that a change in liver function will affect the excretion of belimumab from the body.
Other characteristics of patients

Sex, race or ethnicity of patients did not significantly affect the pharmacokinetics of belimumab when administered intravenously.
The change in the effect of belimumab in intravenous administration, depending on the size of the body, is corrected by calculating the dose based on body weight.
INDICATIONS

- to reduce the activity of the disease in adult patients receiving standard therapy, with active systemic lupus erythematosus (SLE) and the presence of autoantibodies.

DOSING MODE

Consider the possibility of abolishing Benlist ® treatment in the absence of better control of the disease after 6 months of therapy.

The drug Benlista ® is administered IV infusion, before administration it must be reconstituted (dissolved) and diluted.

Infusion should be performed under the careful supervision of medical personnel and prepare everything necessary to treat hypersensitivity reactions, including anaphylaxis.

Infusion of the Benlist ® preparation should be performed within 1 hour.
The drug Benlista ® should not be injected intravenously in 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 a potentially life-threatening adverse reaction develops in the patient (see "Contraindications", "Special instructions").
Patients should be monitored during the administration of Benlist® and after administration during the appropriate period (see "Special instructions", "Side effects").

Premedication: before pre-infusion of Benlist ® preparation, premedication can be performed using oral histamine H 1 receptor blockers in combination with or without antipyretic agents (see section "Special instructions").

Adults

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 administered indefinitely.
Special patient groups

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

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 kidney failure. Dose adjustments in the treatment of patients with renal insufficiency are not required (see section "Pharmacokinetics").
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, as well as 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 correction in individuals with hepatic insufficiency.
Restoration and breeding

The drug Benlist ® does not contain preservatives, therefore, the reconstitution and 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.

It is recommended to use a needle of 21-25 caliber for piercing the bottle stopper during restoration and dilution.

120 mg of belimumum in a single-use vial should be reconstituted in 1.5 ml of sterile water for injection to reach a final concentration of 80 mg / ml of belimumum.400 mg of belimumum in a single-use vial should be reconstituted in 4.8 mL of sterile water for injection to reach a final concentration of 80 mg / mL of belimumum.

To reduce the formation of foam, a sterile water stream should be directed to the wall of the vial.
The contents of the vial are gently stirred in a circular motion for 60 seconds. To restore the contents, leave the vial at room temperature, gently stirring in a circular motion for 60 seconds every 5 minutes until the lyophilisate is completely dissolved. Do not shake the bottle.
The recovery process usually takes 10 to 15 minutes after the addition of sterile water, but can last up to 30 minutes.
Protect the reconstituted solution from direct sunlight.
If a mechanical device is used to restore the drug, the rotation speed 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 a 0.9% solution of sodium chloride (normal saline) for intravenous infusions.

Do not use a 5% dextrose solution for intravenous administration, since it is incompatible with belimumab.

From an infusion tank containing 250 ml of normal saline, a volume equal to the volume of the reconstituted solution of belimumab, which is required to administer the dose of the drug calculated for the patient, is recovered and utilized.
Then, the required volume of reconstituted solution of belimumab is added to this infusion vessel. Gently invert the container to mix the solution. Unused residues of the solution of belimumab in vials should be disposed of.
Before use, visually check the solution of belimumab for visible particles and discoloration.
In the presence of visible particles or discoloration, the solution is disposed of.
If the reconstituted drug solution is not used immediately, it should be protected from direct sunlight and stored in the refrigerator at a temperature of 2 ° to 8 ° C.
The drug diluted with normal saline can be stored both at a temperature of 2 ° to 8 ° C and at room temperature.
The total time from the time of reconstitution to completion of infusions should not exceed 8 hours.

Introduction

Infusion of the Benlist ® preparation should be performed within 1 hour.

The drug Benlista ® should not be administered concomitantly with other drugs through the same dropper.
Studies of physical or biochemical compatibility for the analysis of co-administration of belimumab with other drugs have not been conducted.
There was no incompatibility of belimumab with PVC or polyolefin containers.

SIDE EFFECT

The safety of the use of belimumab in patients with SLE was evaluated based on three placebo-controlled studies of belimumab for IV administration.

The data below show the results of the use of belimumab (10 mg / kg IV for 1 hour on treatment days 0, 14, 28, and then every 28 days for 52 weeks) in 674 patients with SLE, including 472 patients taking belimumab up to 52 weeks.
The presented safety data include data obtained with the use of belimumab for more than 52 weeks in some patients, as well as post-registration data.
The majority of patients simultaneously received concomitant treatment with drugs from one or more of the following groups: SCS, immunomodulators, antimalarials, NSAIDs.

The undesirable reactions 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 (? 1/1 000 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.
From the immune system: often - hypersensitivity reactions *;
infrequently - anaphylaxis, angioedema.
Skin and subcutaneous tissue disorders: rare - rash, hives.
General disorders and the site of injection: often - fever, systemic infusion reactions *.
Infectious and parasitic diseases: very often - infections.
* "Hypersensitivity reactions" include a group of terms, including anaphylaxis, and may be manifested as a series of symptoms such as hypotension, angioedema, urticaria or any other rashes, itching and dyspnea. "Systemic infusion reactions' covers a group of terms and can manifest itself in the form of a number of symptoms including bradycardia, myalgia, headache, rash, hives, fever, arterial hypo- or hypertension, dizziness and pain in the joints. Due to the overlap of signs and symptoms it is not possible to distinguish between hypersensitivity reactions and systemic infusion reactions in each case.
hypersensitivity reactions
In 0.4% of patients have been reported clinically significant hypersensitivity reactions associated with the on / in the belimumab and demanded a complete withdrawal of the drug. Typically, such reactions have been observed in the infusion day, and patients with a history of a lot of episodes of drug allergies or significant hypersensitivity may be at increased risk. Observed delay the onset of acute hypersensitivity reaction for several hours after infusion, and repetition of clinically relevant reactions following the resolution of the primary reaction of symptoms on a corresponding treatment. There were also non-sharp delayed-type hypersensitivity manifested by symptoms such as rash, nausea, fatigue, myalgia, headache and facial swelling.
infection
Belimumab In clinical studies for on / in the overall rate of infection was 70% in the group receiving belimumab, and 67% in the placebo group. Following infection occurred at least 3% of patients receiving belimumab, and at least 1% more frequently than patients receiving placebo: nasopharyngitis, bronchitis, pharyngitis, cystitis, and gastroenteritis viral. Serious infections occurred in 5% of patients receiving placebo or belimumab; among them serious opportunistic infections were less than 1% and 0% respectively. Some infections have been severe or fatal.
CONTRAINDICATIONS

- belimumab hypersensitivity to the drug or one of the components;
- children's age till 18 years;

- active forms infectious, and neoplastic diseases of immunodeficiency.
Carefully

Heavy active lupus CNS, kidney; HIV infection; hypogammaglobulinemia (IgG <400 mg / ml); IgA deficiency (IgA <10 mg / ml); transplant large body of hematopoietic stem cells, bone marrow or kidney (history).
Belimumab simultaneous use with other drugs aimed at suppressing the activity of B-lymphocytes or from I / cyclophosphamide not studied. Caution should be exercised when treating both belimumab and other drugs aimed at suppressing the activity of B-lymphocytes, or cyclophosphamide.
The risk of infections.As is the case with other immunomodulating agents, belimumab, according to its mechanism of action may increase the risk of infections. It reported on the development of severe infections, including fatal, in patients with SLE receiving therapy with immunosuppressive agents, including belimumab (see. section "Side effects") . You should carefully monitor patients who during treatment with belimumab has developed an infectious disease, and consider discontinuation of therapy immunosuppressants. Physicians should exercise caution in the appointment of belimumab in patients with severe or chronic infections.
Growth of malignant tumors.As is the case with other immunomodulating agents, belimumab, according to its mechanism of action may increase the potential risk of malignant tumors. In clinical studies, there was no marked difference in the frequency of occurrence of cancer patients among the groups receiving belimumab treatment and placebo.
Immunization.It should not be vaccinated with live vaccines within 30 days prior to or during treatment with belimumab, as Clinical safety of such combinations has not been established. There are no data on the secondary transmission of infection from persons who have received the vaccine, patients receiving belimumab. Because of its mechanism of action of belimumab could disrupt response to immunization. However, according to a clinical study conducted to evaluate the response to the 23-valent pneumococcal vaccine, the overall immune responses to different serotypes were similar in patients with SLE treated and not treated with belimumab during vaccination. The limited data suggest that belimumab has little effect on the ability to maintain a protective immune response upon immunization, carried to the destination belimumab.
PREGNANCY AND LACTATION

Fertility
There are no data on the effect of belimumab on fertility in humans. In animal studies, effects on fertility in males and females was not evaluated.
Pregnancy
Data on the use of belimumab are limited in pregnant women; formal studies have been conducted. Antibodies group of immunoglobulins G (IgG), including belimumab, can cross the placenta. Belimumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If preventing pregnancy is justified, women of childbearing potential should use effective methods of contraception during use of belimumab and for at least 4 months after the last injection.
In animal studies there was no evidence of direct or indirect harmful effects of the drug with respect to toxicity to the mother's body, pregnancy or fetal development. Associated with the introduction of changes in the body the drug infant monkeys limited reversible decrease in the number of B-lymphocytes. It is necessary to control the reduction in the number of B lymphocytes in the blood of infants whose mothers were treated belimumab, and depending on the results, consider postponing infants vaccinated live virus vaccines. Reducing the number of B-lymphocytes in infants can also disrupt response to immunization (see. Section "Special instructions").
Breastfeeding
Security applications belimumab during breast-feeding has not been established. Data on the allocation of belimumab milk of women or sucking belimumab in systemic circulation after feeding absent.
It is recommended to make a decision about treatment belimumab during breastfeeding, considering the importance of breastfeeding for the child, the importance of the drug to the mother and any possible adverse impact of belimumab or basic status of the mother of a child who is breastfed.
APPLICATION FOR FUNCTIONS OF THE LIVER

Formal studies belimumab use for the treatment of patients with systemic lupus erythematosus with renal impairment have been conducted. The study of belimumab actions carried out in a limited number of patients with SLE and renal events. Dose adjustment in patients with renal impairment is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Belimumab formal studies have use in the treatment of patients with systemic lupus erythematosus with hepatic insufficiency was conducted. However, according to results of clinical trials of the functional state of the liver had no significant effect on the pharmacokinetics of belimumab. Given these results and the fact that, in general, the liver is not directly involved in the clearance of the antibody, it can be assumed that the need for dose adjustment in patients with hepatic impairment is virtually nonexistent.
APPLICATION FOR CHILDREN

The use of belimumab in patients younger than 18 years have not been studied. Data on the safety and efficacy of belimumab in patients in this age group are not available.
APPLICATION IN ELDERLY PATIENTS

Despite the fact that data on the use of the drug in elderly patients are limited, not recommended for dose adjustment.
SPECIAL INSTRUCTIONS

Belimumab introduction can lead to the development of systemic infusion reactions and hypersensitivity reactions which can be severe or fatal result. In case of severe reactions to interrupt administration of belimumab and assign the appropriate medical therapy. Patients with a history of several cases of drug allergies or significant hypersensitivity may be at increased risk (see. Section "Side effects").
Systemic infusion reactions and hypersensitivity reactions occurred more frequently during the introduction of the first two doses, with each subsequent dose showed a trend to fewer reactions. There have been episodes of delayed onset of acute hypersensitivity reactions. Patients receiving belimumab, should be aware of the potential danger, the signs and symptoms of such reactions, as well as the need for immediate treatment for medical assistance. Symptoms may include anaphylactic reactions, bradycardia, hypotension, angioedema and dyspnea. Also available are non-acute delayed type hypersensitivity reactions manifested by symptoms such as rash, nausea, fatigue, myalgia, headache and swelling of the face.
According to clinical studies, serious infusion reactions and severe hypersensitivity reactions developed in less than 1% of patients. Since there have been episodes of delayed onset of acute hypersensitivity reactions, patients should be monitored during intravenous administration of belimumab and after administration over an appropriate period. Belimumab before infusion can be carried premedication with oral histamine H 1 receptors in combination with antipyretic or without it. There is insufficient data to evaluate whether premedication reduces the incidence or severity of infusion reactions.
Progressive multifocal leukoencephalopathy (PML)
Posts have been reported on the development of progressive multifocal leukoencephalopathy (PML), which led to neurological deficits, including fatalities, in patients with SLE receiving immunosuppressive therapy, including belimumab. The presence of PML should be ruled out in any patient with new problems or progressive neurological signs and symptoms. The patient should be examined by a neurologist or other relevant professionals, and in the case of confirmation of the diagnosis of PML should be considered cancellation of immunosuppressive therapy, including belimumab
Impact on the ability to drive vehicles and manage mechanisms

Belimumab studies of the effect on the ability to drive or operate the vehicle mechanical means was conducted. The pharmacological properties of belimumab suggest that it has no adverse effect on the ability to perform such activities.
When considering the patient's ability to perform tasks that require more concentration, complex motor or cognitive skills necessary to take into account the patient's clinical condition and safety of belimumab profile.
OVERDOSE

There are limited data on overdose belimumab. Adverse reactions identified in relation to cases of overdose, consistent with expected when applying belimumab.
Patients receiving two doses of 20 mg / kg body weight of the drug in the form of on / in infusion at intervals of 21 days, no increase in the frequency or severity of adverse reactions compared to patients receiving the drug in doses of 1, 4 or 10 mg / kg body weight.
DRUG INTERACTION

Research belimumab drug interactions with other drugs have not been conducted.
In clinical studies of patients with SLE simultaneous application mycophenolate mofetil, azathioprine, hydroxychloroquine, methotrexate, NSAIDs, acetyl salicylic acid and HMG-CoA reductase inhibitor had no significant effect on the action of belimumab (cm. "Pharmacokinetics" section).
The drug is incompatible with dextrose.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be protected from light, reach of children at a temperature of from 2 ° to 8 ° C.
Do not freeze. Store in original container until ready to use.
Transported at a temperature of from 2 ° to 8 ° C, protected from light.
Do not freeze. Shelf life - 3 years.
Do not use after the expiration date stated on the package.

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