Benlysta (Solution, Lyophilisate) Instructions for Use

ATC Code

L04AG04 (Belimumab)

Active Substance

Belimumab (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Mechanism of action

B-lymphocyte stimulator (BLyS, also known as BAFF and TNFSF13), a ligand of the tumor necrosis factor (TNF) family, inhibits apoptosis of B-lymphocytes and stimulates the differentiation of B-lymphocytes into immunoglobulin-producing plasma cells. Patients with systemic lupus erythematosus (SLE) exhibit excessive BLyS expression. There is a strong correlation between the degree of SLE activity (based on the Safety of Estrogen in Lupus Erythematosus National Assessment – the Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI]) and plasma BLyS levels.

Belimumab is a fully human monoclonal antibody of the IgG_1λ class that specifically binds to soluble human BLyS and inhibits its biological activity. Belimumab does not bind directly to B-lymphocytes, but by binding to BLyS, Belimumab inhibits the viability of B-lymphocytes, including autoreactive clones, and reduces the differentiation of B-lymphocytes into immunoglobulin-producing plasma cells.

Pharmacodynamics

Reduction of elevated serum levels of IgG and antibodies to native (double-stranded) DNA (anti-dsDNA) was observed starting from week 8 and continued until week 52 of treatment. In patients with hypergammaglobulinemia at baseline who received Belimumab and placebo, normalization of IgG levels by week 52 was observed in 49% and 20% of cases, respectively. In the belimumab group, among patients with baseline anti-dsDNA, there was a decrease in the number of patients with anti-dsDNA compared to baseline; the reduction became apparent starting from week 8, and by week 52, anti-dsDNA became undetectable in 16% of patients treated with belimumab and in 7% of patients receiving placebo.

In patients with low baseline complement levels, therapy with Benlysta^® was accompanied by an increase in its level, starting from week 4 and throughout the subsequent period. By week 52, C3 and C4 levels normalized in 38% and 44% of patients receiving Belimumab, respectively, compared with 17% and 19% of patients receiving placebo.

The target of belimumab is BLyS, a cytokine critical for the survival, differentiation and proliferation of B-lymphocytes. Belimumab significantly reduced the number of circulating B-lymphocytes, naive and activated forms, plasma cells, and the lupus B-lymphocyte subpopulation at week 52. A decrease in the number of naive, plasma and short-lived plasma cells, as well as the lupus B-lymphocyte subpopulation, was observed starting from week 8. The number of memory cells initially increased, then slowly decreased to baseline by week 52.

In a long-term uncontrolled extension study, B-lymphocyte counts (including naive and activated forms, plasma cells, and the lupus B-lymphocyte subpopulation) and IgG concentration were observed for more than 7 years of therapy. After more than 7 years of treatment, a significant and sustained reduction in B-lymphocyte counts in various subpopulations was observed, with a median reduction of 87% for naive B-lymphocytes, 67% for memory B-lymphocytes, 99% for activated B-lymphocytes, and 92% for plasma cells. After approximately 7 years, the median reduction in IgG concentration was 28% and was observed in 1.6% of patients with IgG concentration falling below 400 mg/dL. Throughout the study, the described frequency of adverse reactions generally remained unchanged or decreased.

Immunogenicity

In two phase III studies of intravenous belimumab, persistent anti-belimumab antibody formation was observed in 4 out of 563 (0.7%) patients receiving the drug at a dose of 10 mg/kg and in 27 out of 559 (4.8%) patients receiving the drug at a dose of 1 mg/kg. The reported frequency in the group of patients receiving Belimumab 10 mg/kg may be lower than the actual frequency due to reduced sensitivity of the assay in the presence of high drug concentrations.

Neutralizing antibodies were detected in 3 patients receiving intravenous Belimumab at a dose of 1 mg/kg. However, the presence of anti-belimumab antibodies in patients receiving intravenous Belimumab was relatively infrequent, so due to the small number of patients with antibodies, no definitive conclusions can be drawn regarding the impact of immunogenicity on the pharmacokinetics of belimumab.

Pharmacokinetics

The pharmacokinetic parameters presented below are based on population estimated parameters for 563 patients who received Belimumab intravenously at a dose of 10 mg/kg in two phase III clinical studies.

Absorption

Following IV administration, the C_max of belimumab in serum was typically observed at the end of the infusion or shortly after its completion. Based on modeling of the drug concentration versus time curve using typical parameter values from the population pharmacokinetic model, the C_max in serum was 313 µg/mL.

Distribution

Belimumab was distributed in tissues with a total V_d of 5.29 L.

Metabolism

Belimumab is a protein, and its presumed metabolic pathway involves breakdown into small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies of the drug have not been conducted.

Elimination

Following IV administration, the decrease in belimumab serum concentration was biexponential with a distribution half-life of 1.75 days and a terminal T_1/2 of 19.4 days. Systemic clearance was 215 mL/day.

Drug Interactions

Concomitant use of mycophenolate mofetil, azathioprine, methotrexate, and hydroxychloroquine does not significantly affect the pharmacokinetics of intravenous belimumab, as evidenced by population pharmacokinetic analysis. A wide range of other drugs (NSAIDs, acetylsalicylic acid, HMG-CoA reductase inhibitors) also do not significantly affect the pharmacokinetics of belimumab. Concomitant use of corticosteroids and ACE inhibitors during population pharmacokinetic analysis of intravenous administration led to a statistically significant increase in systemic clearance. However, the effects of corticosteroids and ACE inhibitors with intravenous belimumab administration were not clinically significant, as the magnitude of the deviations was within the natural variability of clearance parameters.

Pharmacokinetics in Special Clinical Cases

Elderly patients

The use of belimumab has been studied in a limited number of elderly patients. In a population pharmacokinetic analysis of the general SLE patient population receiving the drug intravenously in studies, age did not affect belimumab exposure. However, given the small number of patients aged 65 years and older, the influence of age cannot be definitively excluded.

Children and adolescents

Information on the pharmacokinetics of the drug in pediatric patients is not available.

Patients with renal impairment

No formal studies have been conducted to investigate the effect of renal failure on the pharmacokinetics of belimumab. During clinical studies, intravenous Belimumab was studied in a limited number of patients with SLE and renal impairment (CrCl <60 mL/min, including a small number of patients with CrCl <30 mL/min). With intravenous administration, proteinuria (at least 2 g/day) led to an increase in belimumab clearance, and a decrease in CrCl led to a decrease in belimumab clearance. These changes were within the expected range of variability for intravenous administration. Therefore, dose adjustment in patients with renal impairment is not required.

Patients with hepatic impairment

No formal studies have been conducted to investigate the effect of hepatic impairment on the pharmacokinetics of belimumab. IgG₁ molecules, such as Belimumab, are broken down by widely distributed proteolytic enzymes that are present not only in liver tissue; therefore, it is unlikely that changes in liver function will affect the elimination of belimumab from the body.

Other patient characteristics

Gender, race, or ethnicity of patients did not significantly affect the pharmacokinetics of intravenous belimumab. The variation in the effect of intravenous belimumab depending on body size is corrected by calculating the dose based on body weight.

Indications

• For reducing disease activity in adult patients receiving standard therapy, with active systemic lupus erythematosus (SLE) and the presence of autoantibodies.

ICD codes

Dosage Regimen

Solution

IV infusion: the recommended dose is 10 mg/kg at 2-week intervals for the first three infusions, with subsequent infusions at 4-week intervals.

SC: 200-400 mg once a week in the abdomen or thigh.

Lyophilisate

Discontinuation of treatment with Benlysta^® should be considered if there is no improvement in disease control after 6 months of therapy.

Benlysta^® is administered by intravenous infusion; it must be reconstituted (dissolved) and diluted prior to administration.

The infusion should be performed under the close supervision of healthcare professionals and all necessary equipment for the treatment of hypersensitivity reactions, including anaphylaxis, should be prepared.

Benlysta^® infusion should be administered over 1 hour. Benlysta^® should not be administered by intravenous push or bolus.

If an infusion reaction occurs in a patient, the infusion rate may be reduced or the administration may be interrupted. The infusion should be immediately discontinued if the patient develops a potentially life-threatening adverse reaction (see sections “Contraindications”, “Special Instructions”).

Patients should be monitored during the administration of Benlysta^® and for an appropriate period after administration (see sections “Special Instructions”, “Adverse Reactions”).

Premedication: Premedication with oral histamine H₁ receptor blockers with or without an antipyretic may be administered prior to Benlysta^® infusion (see section “Special Instructions”).

Adults

The recommended dose is 10 mg/kg on treatment days 0, 14, and 28 and then once every 4 weeks. The drug should be administered indefinitely.

Special patient groups

The use of belimumab in patients under 18 years of age has not been studied. There are no data on the safety and efficacy of belimumab in patients of this age group.

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

No formal studies have been conducted on the use of belimumab for the treatment of patients with systemic lupus erythematosus with renal impairment. The effect of belimumab was studied in a limited number of patients with SLE and renal impairment. Dose adjustment is not required when treating patients with renal impairment (see section “Pharmacokinetics”).

No formal studies have been conducted on the use of belimumab for the treatment of patients with systemic lupus erythematosus with hepatic impairment. However, according to the results of clinical studies, liver function did not significantly affect the pharmacokinetics of belimumab. Given these results, as well as the fact that, in general, the liver is not directly involved in the clearance of antibodies, it can be considered that there is practically no need for dose adjustment in individuals with hepatic impairment.

Reconstitution and dilution

Benlysta^® does not contain preservatives, so reconstitution and dilution of the drug should be performed under aseptic conditions.

The vial should be allowed to warm to room temperature for 10-15 minutes.

It is recommended to use a 21-25 gauge needle for piercing the vial stopper during reconstitution and dilution.

120 mg of belimumab in a single-use vial should be reconstituted with 1.5 mL of Sterile Water for Injections to achieve a final belimumab concentration of 80 mg/mL. 400 mg of belimumab in a single-use vial should be reconstituted with 4.8 mL of Sterile Water for Injections to achieve a final belimumab concentration of 80 mg/mL.

To reduce foaming, the stream of sterile water should be directed against the wall of the vial. The contents of the vial are gently mixed by swirling for 60 seconds. To reconstitute the contents, the vial should be left at room temperature, gently swirling every 5 minutes for 60 seconds until the lyophilisate is completely dissolved. The vial should not be shaken.

The reconstitution process usually takes from 10 to 15 minutes after adding sterile water, but may take up to 30 minutes. The reconstituted solution should be protected from direct sunlight.

If a mechanical device is used to reconstitute the drug, the rotation speed should not exceed 500 rpm, and the vial rotation time should not exceed 30 minutes.

The reconstituted solution should be opalescent, colorless to pale yellow, and free of visible particles. However, the presence of small air bubbles in the solution is expected and acceptable.

The resulting solution is diluted to 250 mL with 0.9% sodium chloride solution (normal saline) for intravenous infusion.

5% dextrose solution for intravenous administration should not be used as it is incompatible with belimumab.

From the infusion bag containing 250 mL of normal saline, withdraw and discard a volume equal to the volume of the reconstituted belimumab solution required to administer the dose calculated for the patient. Then add the required volume of the reconstituted belimumab solution to this infusion bag. Gently invert the bag to mix the solution. Unused remnants of belimumab solution in vials should be discarded.

Before use, visually inspect the belimumab solution for visible particles and discoloration. If visible particles or discoloration are present, discard the solution.

If the reconstituted drug solution is not used immediately, it should be protected from direct sunlight and stored refrigerated at a temperature of 2°C (35.6°F) to 8°C (46.4°F). The drug diluted with normal saline can be stored either at 2°C (35.6°F) to 8°C (46.4°F) or at room temperature.

The total time from the moment of reconstitution of the drug to the completion of the infusion should not exceed 8 hours.

Administration

Benlysta^® infusion should be administered over 1 hour.

Benlysta^® should not be administered concurrently with other drugs through the same infusion line. Studies of physical or biochemical compatibility for the analysis of co-administration of belimumab with other drugs have not been conducted.

No incompatibility of belimumab with PVC or polyolefin containers has been observed.

Adverse Reactions

The safety of belimumab in patients with SLE was evaluated based on three placebo-controlled studies of intravenous belimumab.

The data below reflect the results of belimumab use (10 mg/kg IV over 1 hour on treatment days 0, 14, 28, and then every 28 days for 52 weeks) in 674 patients with SLE, including 472 patients who received Belimumab for up to 52 weeks. The presented safety data include data obtained from the use of belimumab for more than 52 weeks in some patients, as well as post-marketing surveillance data.

Most patients were concurrently receiving concomitant treatment with drugs from one or more of the following groups: corticosteroids, immunomodulators, antimalarials, NSAIDs.

The adverse reactions presented below are listed according to the affected organs and organ systems and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000), very rare (<1/10,000, including isolated cases). Frequency categories were formed based on clinical studies of the drug.

Immune system disorders: common – hypersensitivity reactions*; uncommon – anaphylactic reactions, angioedema.

Skin and subcutaneous tissue disorders: uncommon – rash, urticaria.

General disorders and administration site conditions: common – pyrexia, systemic infusion reactions*.

Infections and infestations: very common – infections.

* “Hypersensitivity reactions” include a group of terms, including anaphylaxis, and may manifest as a range of symptoms such as arterial hypotension, angioedema, urticaria or other rashes, pruritus, and dyspnea. “Systemic infusion reactions” cover a group of terms and may manifest as a range of symptoms including bradycardia, myalgia, headache, rash, urticaria, pyrexia, arterial hypo- or hypertension, dizziness, and arthralgia. Due to the overlap of signs and symptoms, it is not possible to distinguish between hypersensitivity reactions and systemic infusion reactions in every case.

Hypersensitivity reactions

Clinically significant hypersensitivity reactions associated with intravenous belimumab administration and requiring complete discontinuation of the drug were reported in 0.4% of patients. Typically, such reactions were observed on the day of infusion, and patients with a history of multiple episodes of drug allergy or significant hypersensitivity may be at increased risk. Delayed onset of acute hypersensitivity reactions several hours after infusion and recurrence of clinically significant reactions after resolution of symptoms of the initial reaction despite appropriate treatment have been observed. Non-acute delayed-type hypersensitivity reactions have also occurred, manifesting with symptoms such as rash, nausea, fatigue, myalgia, headache, and facial edema.

Infections

In clinical studies of intravenous belimumab, the overall incidence of infections was 70% in the Belimumab group and 67% in the placebo group. The following infections occurred in at least 3% of patients taking Belimumab and at least 1% more frequently than in patients taking placebo: nasopharyngitis, bronchitis, pharyngitis, cystitis, and viral gastroenteritis. Serious infections occurred in 5% of patients receiving Belimumab or placebo; among these, serious opportunistic infections accounted for less than 1% and 0%, respectively. Some infections were severe or fatal.

Contraindications

• Hypersensitivity to belimumab or one of the components of the drug;
• Children under 18 years of age;
• Active forms of infectious, immunodeficiency, and tumor diseases.

With caution

Severe active lupus central nervous system, renal involvement; HIV infection; hypogammaglobulinemia (IgG < 400 mg/ml); IgA deficiency (IgA < 10 mg/ml); history of major organ transplantation, hematopoietic stem cell transplantation, bone marrow transplantation, or kidney transplantation.

Concomitant use of belimumab with other drugs aimed at suppressing B-lymphocyte activity, or with intravenous cyclophosphamide has not been studied. Caution should be exercised when treating concomitantly with belimumab and other drugs aimed at suppressing B-lymphocyte activity or with cyclophosphamide.

Risk of infections. As with other immunomodulatory agents, Belimumab, based on its mechanism of action, may increase the risk of infections. Severe, including fatal, infections have been reported in patients with SLE receiving immunosuppressant therapy, including Belimumab (see section “Adverse Reactions”) . Patients who develop an infection during treatment with belimumab should be closely monitored and consideration should be given to discontinuing immunosuppressant therapy. Physicians should exercise caution when prescribing belimumab to patients with severe or chronic infections.

Malignancy growth. As with other immunomodulatory agents, Belimumab, based on its mechanism of action, may increase the potential risk of malignancy. In clinical studies, no difference in the incidence of malignancies was observed between patient groups treated with belimumab and placebo groups.

Immunization. Vaccination with live vaccines should not be administered 30 days before or during treatment with belimumab, as the clinical safety of this combination has not been established. There are no data on secondary transmission of infection from vaccinated individuals to patients receiving Belimumab. Due to its mechanism of action, Belimumab may impair the response to immunization. However, according to a clinical study evaluating the response to the 23-valent pneumococcal vaccine, overall immune responses to various serotypes were similar in SLE patients receiving and not receiving Belimumab during vaccination. Limited data suggest that Belimumab has little effect on the ability to maintain a protective immune response to immunization administered prior to belimumab initiation.

Use in Pregnancy and Lactation

Fertility

There are no data on the effect of belimumab on human fertility. In animal studies, the effect on male and female fertility was not evaluated.

Pregnancy

Data on the use of belimumab in pregnant women are limited; no formal studies have been conducted. Immunoglobulin G (IgG) antibodies, 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 pregnancy prevention is warranted, women of childbearing potential should use effective contraception during belimumab use and for at least 4 months after the last administration of the drug.

Animal studies revealed no direct or indirect harmful effects of the drug with respect to maternal toxicity, pregnancy course, or intrauterine fetal development. Drug-related changes in infant monkeys were limited to a reversible decrease in B-lymphocyte count. Decreased B-lymphocyte counts in the blood of infants whose mothers received belimumab therapy should be monitored, and depending on the results, consideration should be given to delaying vaccination of infants with live viral vaccines. Decreased B-lymphocyte counts in infants may also impair the response to immunization (see section “Special Precautions”).

Breastfeeding period

The safety of belimumab during breastfeeding has not been established. There are no data regarding the excretion of belimumab in human milk or the absorption of belimumab into the systemic circulation after breastfeeding.

The decision to use belimumab during breastfeeding should be made considering the importance of breastfeeding for the child, the importance of the drug for the mother, and any potential adverse effects of belimumab or the mother’s underlying condition on the breastfed child.

Use in Hepatic Impairment

No formal studies have been conducted on the use of belimumab for the treatment of patients with systemic lupus erythematosus with hepatic impairment. However, according to the results of clinical studies, liver function did not have a significant effect on the pharmacokinetics of belimumab. Given these results, as well as the fact that, in general, the liver is not directly involved in the clearance of antibodies, it can be considered that there is practically no need for dose adjustment in individuals with hepatic impairment.

Use in Renal Impairment

No formal studies have been conducted on the use of belimumab for the treatment of patients with systemic lupus erythematosus with renal impairment. The effect of belimumab was studied in a limited number of patients with SLE and renal impairment. No dose adjustment is required when treating patients with renal impairment.

Pediatric Use

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

Geriatric Use

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

Special Precautions

Administration of belimumab may lead to the development of systemic infusion reactions and hypersensitivity reactions, which may be severe or fatal. In case of a severe reaction, belimumab administration should be interrupted and appropriate drug therapy should be administered. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk (see section “Adverse Reactions”).

Systemic infusion reactions and hypersensitivity reactions occurred more frequently during the administration of the first two doses, with a trend towards a decrease in the number of reactions with each subsequent dose. There have been episodes of delayed onset of acute hypersensitivity reactions. Patients receiving Belimumab should be informed about the potential risk, signs and symptoms of such reactions, and the need to seek immediate medical attention. Symptoms may include anaphylactic reactions, bradycardia, arterial hypotension, angioedema, and dyspnea. Non-acute delayed-type hypersensitivity reactions are also possible, manifesting with symptoms such as rash, nausea, fatigue, myalgia, headache, and facial edema.

According to clinical studies, serious infusion reactions and serious hypersensitivity reactions occurred in less than 1% of patients. Since there have been episodes of delayed onset of acute hypersensitivity reactions, patients should be monitored during the intravenous infusion of belimumab and for an appropriate period after the end of the infusion. Premedication with oral histamine H₁-receptor blockers with or without an antipyretic may be administered prior to belimumab infusion. There are insufficient data to assess whether premedication reduces the frequency or severity of infusion reactions.

Progressive multifocal leukoencephalopathy (PML)

There have been reports of progressive multifocal leukoencephalopathy (PML), which led to neurological deficits, including fatal outcomes, in patients with SLE receiving immunosuppressive therapy, including Belimumab. PML should be excluded in any patient with new or progressive neurological signs and symptoms. The patient should be examined by a neurologist or other appropriate specialist and, if PML is confirmed, consideration should be given to discontinuing immunosuppressive therapy, including belimumab.

Effect on ability to drive and operate machinery

No studies have been conducted on the effect of belimumab on the ability to drive a car or operate machinery. The pharmacological properties of belimumab suggest that it does not have a negative effect on the ability to perform such activities.

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

Overdose

There are limited data on belimumab overdose. Adverse reactions noted in connection with overdose cases are consistent with those expected with belimumab use.

In patients who received two doses of the drug of 20 mg/kg body weight as intravenous infusions with an interval of 21 days, no increase in the frequency or severity of adverse reactions was observed compared to patients who received the drug at doses of 1, 4, or 10 mg/kg body weight.

Drug Interactions

No studies of drug interactions of belimumab with other drugs have been conducted.

In clinical studies in patients with SLE, concomitant use of mycophenolate mofetil, azathioprine, hydroxychloroquine, methotrexate, NSAIDs, acetylsalicylic acid, and HMG-CoA reductase inhibitors did not have a significant effect on the action of belimumab (see section “Pharmacokinetics”).

The drug is incompatible with dextrose.

Storage Conditions

The drug should be stored in a place protected from light, out of the reach of children, at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze. Store in the original packaging until use.

Transport at a temperature between 2°C (35.6°F) and 8°C (46.4°F), protected from light. Do not freeze.

Shelf Life

The shelf life is 3 years.

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

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.