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Benlysta斑麗達

Benlysta

belimumab

Manufacturer:

GlaxoSmithKline

Distributor:

Zuellig
/
Agencia Lei Va Hong
Full Prescribing Info
Contents
Belimumab.
Description
Each 120 mg or 400 mg vial contains 120 mg or 400 mg of belimumab, respectively. After reconstitution, the solution contains 80 mg belimumab per ml.
Each 1-ml pre-filled pen contains 200 mg of belimumab.
Belimumab is a human, IgG1λ monoclonal antibody, produced in a mammalian cell line (NS0) by recombinant DNA technology.
Excipients/Inactive Ingredients: Powder for concentrate for solution for infusion: Citric acid monohydrate (E330), Sodium citrate (E331), Sucrose, Polysorbate 80.
Solution for injection: L-arginine hydrochloride, L-histidine, L-histidine monohydrochloride, Polysorbate 80, Sodium chloride, Water for injection.
Action
Pharmacotherapeutic group: Selective immunosuppressants. ATC code: L04AA26.
Pharmacology: Pharmacodynamics: Mechanism of action: Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B Lymphocyte Stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab blocks the binding of soluble BLyS, a B cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.
BLyS levels are elevated in patients with SLE and other autoimmune diseases. There is an association between plasma BLyS levels and SLE disease activity. The relative contribution of BLyS levels to the pathophysiology of SLE is not fully understood.
Pharmacodynamic effects: Powder for concentrate for solution for infusion: Changes in biomarkers were seen in clinical trials with Benlysta administered intravenously. In adult patients with hypergammaglobulinemia, normalization of IgG levels was observed by Week 52 in 49% and 20% of patients receiving Benlysta and placebo, respectively.
In patients with anti-dsDNA antibodies, 16% of patients treated with Benlysta converted to anti-dsDNA negative compared with 7% of the patients receiving placebo by Week 52.
In patients with low complement levels, normalization of C3 and C4 was observed by Week 52 in 38% and 44% of patients receiving Benlysta and in 17% and 18% of patients receiving placebo, respectively.
Of the anti-phospholipid antibodies, only anti-cardiolipin antibody was measured. For anti-cardiolipin IgA antibody a 37% reduction at Week 52 was seen (p=0.0003), for anti-cardiolipin IgG antibody a 26% reduction at Week 52 was seen (p=0.0324) and for anti-cardiolipin IgM a 25% reduction was seen (p=NS, 0.46).
Changes in B cells (including naïve, memory and activated B cells, and plasma cells) and IgG levels occurring in patients during ongoing treatment with intravenous belimumab were followed in a long-term uncontrolled extension study. After 7 and a half years of treatment (including the 72-week parent study), a substantial and sustained decrease in various B cell subsets was observed leading to 87% median reduction in naïve B cells, 67% in memory B cells, 99% in activated B cells, and 92% median reduction in plasma cells after more than 7 years of treatment. After about 7 years, a 28% median reduction in IgG levels was observed, with 1.6% of subjects experiencing a decrease in IgG levels to below 400 mg/dl. Over the course of the study, the reported incidence of AEs generally remained stable or declined.
In one study in paediatric patients (6 to 17 years of age) the pharmacodynamic response was consistent with the adult data.
Solution for injection: Median IgG levels at Week 52 were reduced by 11% in patients receiving Benlysta compared with an increase of 0.7% in patients receiving placebo.
In patients with anti-dsDNA antibodies at baseline, median anti-dsDNA antibodies levels at Week 52 were reduced by 56% in patients receiving Benlysta compared with 41% in patients receiving placebo. In patients with anti-dsDNA antibodies at baseline, by Week 52, 18% of patients treated with Benlysta had converted to anti-dsDNA negative compared with 15% of the patients receiving placebo.
In patients with low complement levels, normalization of C3 and C4 was observed by Week 52 in 42% and 53% of patients receiving Benlysta and in 21% and 20% of patients receiving placebo, respectively.
Benlysta significantly reduced circulating overall, transitional, naïve, and SLE B cells, as well as plasma cells at Week 52. Reductions in naïve and transitional B cells, as well as the SLE B cell subset were observed as early as Week 8. Memory cells increased initially and slowly declined toward baseline levels by Week 52.
The B cell and IgG response to long term treatment with intravenous Benlysta was assessed in an uncontrolled extension study. After 7 and a half years of treatment (including the 72-week parent study), a substantial and sustained decrease in various B cell subsets was observed leading to 87% median reduction in naïve B cells, 67% in memory B cells, 99% in activated B cells, and 92% median reduction in plasma cells after more than 7 years of treatment. After about 7 years, a 28% median reduction in IgG levels was observed, with 1.6% of subjects experiencing a decrease in IgG levels to below 400 mg/dl. Over the course of the study, the reported incidence of AEs generally remained stable or declined.
Immunogenicity: Powder for concentrate for solution for infusion: Assay sensitivity for neutralising antibodies and non-specific anti-drug antibody (ADA) is limited by the presence of active drug in the collected samples. The true occurrence of neutralising antibodies and non-specific anti-drug antibody in the study population is therefore not known. In the two Phase III studies, 4 of the 563 (0.7%) patients in the 10 mg/kg group and 27 out of 559 (4.8%) patients in the 1 mg/kg group tested positive for persistent presence of anti-belimumab antibodies. Among persistent-positive subjects in the Phase III studies, 1/10 (10%), 2/27 (7%) and 1/4 (25%) subjects in the placebo, 1 mg/kg and 10 mg/kg groups, respectively, experienced infusion reactions on a dosing day; these infusion reactions were all non-serious and mild to moderate in severity. Few patients with ADA reported serious/severe AEs. The rates of infusion reactions among persistent-positive subjects were comparable to the rates for ADA negative patients of 75/552 (14%), 78/523 (15%), and 83/559 (15%) in the placebo, 1 mg/kg and 10 mg/kg groups, respectively.
In one study in 6 to 17-year-old paediatric patients (n=53), none of the patients developed anti-belimumab antibodies.
Solution for injection: In the subcutaneous study where serum samples from more than 550 patients with SLE were tested, no anti-belimumab antibodies were detected during or after treatment with belimumab 200 mg subcutaneously.
Clinical efficacy and safety: Powder for concentrate for solution for infusion: Intravenous infusion in adults: The efficacy of Benlysta administered intravenously was evaluated in 2 randomized, double-blind, placebo-controlled studies in 1,684 patients with a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) classification criteria. Patients had active SLE disease, defined as a SELENA-SLEDAI (SELENA=Safety of Estrogens in Systemic Lupus Erythematosus National Assessment; SLEDAI=Systemic Lupus Erythematosus Disease Activity Index) score ≥6 and positive anti-nuclear antibody (ANA) test results (ANA titre ≥1:80 and/or a positive anti-dsDNA [≥30 units/ml]) at screening. Patients were on a stable SLE treatment regimen consisting of (alone or in combination): corticosteroids, anti-malarials, NSAIDs or other immunosuppressives. The two studies were similar in design except that BLISS-76 was a 76-week study and BLISS-52 was a 52-week study. In both studies the primary efficacy endpoint was evaluated at 52 weeks.
Patients who had severe active lupus nephritis and patients who had severe active central nervous system (CNS) lupus were excluded.
BLISS-76 was conducted primarily in North America and Western Europe. Background medicinal products included corticosteroids (76%; >7.5 mg/day 46%), immunosuppressives (56%), and anti-malarials (63%).
BLISS-52 was conducted in South America, Eastern Europe, Asia, and Australia. Background medicinal products included corticosteroids (96%; >7.5 mg/day 69%), immunosuppressives (42%), and anti-malarials (67%).
At baseline 52% of patients had high disease activity (SELENA SLEDAI score ≥10), 59% of patients had mucocutaneous, 60% had musculoskeletal, 16% had haematological, 11% had renal and 9% had vascular organ domain involvement (BILAG A or B at baseline).
The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at Week 52 compared with baseline: ≥4-point reduction in the SELENA-SLEDAI score; and no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores; and no worsening (<0.30 point increase) in Physician's Global Assessment score (PGA).
The SLE Responder Index measures improvement in SLE disease activity, without worsening in any organ system, or in the patient's overall condition. (See Table 1.)

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In a pooled analysis of the two studies, the percentage of patients receiving >7.5 mg/day prednisone (or equivalent) at baseline, whose average corticosteroid dose was reduced by at least 25% to a dose equivalent to prednisone ≤7.5 mg/day during Weeks 40 through 52, was 17.9% in the group receiving Benlysta and 12.3% in the group receiving placebo (p=0.0451).
Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The median time to the first flare was delayed in the pooled group receiving Benlysta compared to the group receiving placebo (110 vs 84 days, hazard ratio=0.84, p=0.012). Severe flares were observed in 15.6% of the Benlysta group compared to 23.7% of the placebo group over the 52 weeks of observation (observed treatment difference = - 8.1%; hazard ratio=0.64, p=0.0011).
Benlysta demonstrated improvement in fatigue compared with placebo measured by the FACIT-Fatigue scale in the pooled analysis. The mean change of score at Week 52 from baseline is significantly greater with Benlysta compared to placebo (4.70 vs 2.46, p=0.0006).
Univariate and multivariate analysis of the primary endpoint in pre-specified subgroups demonstrated that the greatest benefit was observed in patients with higher disease activity including patients with SELENA SLEDAI scores ≥ 10, patients requiring steroids to control their disease, and patients with low complement levels.
Post-hoc analysis has identified high responding subgroups such as those patients with low complement and positive anti-dsDNA at baseline, see Table 2 for results of this example of a higher disease activity group. Of these patients, 64.5% had SELENA SLEDAI scores ≥ 10 at baseline. (See Table 2.)

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Solution for injection: Subcutaneous injection: The efficacy of Benlysta administered subcutaneously was evaluated in a randomised, double-blind, placebo-controlled 52-week Phase III study (HGS1006-C1115; BEL112341) in 836 adult patients with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥8 and positive anti-nuclear antibody (ANA or anti-dsDNA) test results (ANA titre ≥1:80 and/or a positive anti-dsDNA [≥30 units/ml]) at screening. Patients were on a stable SLE treatment regimen (standard of care) consisting of any of the following (alone or in combination): corticosteroids, anti-malarials, NSAIDs or other immunosuppressives. Patients were excluded from the study if they had severe active central nervous system lupus or severe active lupus nephritis.
This study was conducted in the US, South America, Europe and Asia. Patient median age was 37 years (range: 18 to 77 years), and the majority (94%) were female. Background medicinal products included corticosteroids (86%; >7.5 mg/day prednisone equivalent 60%), immunosuppressives (46%), and anti-malarials (69%). Patients were randomised in a 2:1 ratio to receive belimumab 200 mg or placebo subcutaneously once weekly for 52 weeks.
At baseline 62.2% of patients had high disease activity (SELENA SLEDAI score ≥10), 88% of patients had mucocutaneous, 78% had musculoskeletal, 8% had haematological, 12% had renal, and 8% had vascular organ involvement.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at Week 52 compared with baseline: ≥4-point reduction in the SELENA-SLEDAI score; and no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores; and no worsening (<0.30 point increase) in Physician's Global Assessment score (PGA).
The SLE Responder Index measures improvement in SLE disease activity, without worsening in any organ system, or in the patient's overall condition. (See Table 3.)

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All patients received standard therapy.
The differences between the treatment groups were apparent by Week 16 and sustained through Week 52 (see figure).

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Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The risk of first flare was reduced by 22% during the 52 weeks of observation in the group receiving Benlysta compared with the group receiving placebo (hazard ratio=0.78; p=0.0061). The median time to the first flare among patients having a flare was delayed in patients receiving Benlysta compared with placebo (190 days vs. 141 days).
Severe flares were observed in 10.6% of patients in the group receiving Benlysta compared with 18.2% of patients in the group receiving placebo over the 52 weeks of observation (observed treatment difference = -7.6%). The risk of severe flares was reduced by 49% during the 52 weeks of observation in the group receiving Benlysta compared with the group receiving placebo (hazard ratio=0.51; p=0.0004). The median time to the first severe flare among patients having a severe flare was delayed in patients receiving Benlysta compared with placebo (171 days vs. 118 days).
The percentage of patients receiving greater than 7.5 mg/day prednisone (or equivalent) at baseline whose average corticosteroid dose was reduced by at least 25% from baseline to a dose equivalent to prednisone ≤7.5 mg/day during Weeks 40 through 52, was 18.2% in the group receiving Benlysta and 11.9% in the group receiving placebo (p=0.0732).
Benlysta demonstrated improvement in fatigue compared with placebo measured by the FACIT-Fatigue Scale. The adjusted mean change of score at Week 52 from baseline is significantly greater with Benlysta compared to placebo (4.4 vs. 2.7, p=0.0130).
Subgroup analysis of the primary endpoint demonstrated that the greatest benefit was observed in patients with higher disease activity at baseline including patients with SELENA SLEDAI scores ≥ 10 or patients requiring steroids to control their disease or patients with low complement levels.
An additional, previously identified serologically active group, those patients with low complement and positive anti-dsDNA at baseline, also demonstrated a greater relative response, see Table 4 for results of this example of a higher disease activity group. (See Table 4.)

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Age and race: Powder for concentrate for solution for infusion: Age: There were too few patients ≥65 years of age enrolled in the controlled clinical trials to draw meaningful conclusions about the effects of age on clinical outcomes.
Black patients: Benlysta was administered intravenously to black patients in a randomised (2:1), double-blind, placebo-controlled, 52-week Phase III/IV study (EMBRACE). Efficacy was evaluated in 448 patients. The proportion of black patients achieving an SRI-S2K response was higher in patients receiving Benlysta but the difference was not statistically significant compared with placebo. However, consistent with results from other studies, in black patients with high disease activity (low complement and positive anti-dsDNA at baseline, n=141) the SRI-S2K response was 45.1% for Benlysta 10 mg/kg compared with 24.0% for placebo (odds ratio 3.00; 95% CI: 1.35, 6.68).
Solution for injection: There were too few patients ≥65 years of age or black patients enrolled in the controlled clinical trials with subcutaneous Benlysta to draw meaningful conclusions about the effects of age or race on clinical outcomes.
The safety and efficacy of Benlysta administered intravenously have been studied in black patients. The currently available data are described in the prescribing information of Benlysta 120 mg and 400 mg powder for concentrate for solution for infusion.
Paediatric population: Powder for concentrate for solution for infusion: The safety and efficacy of Benlysta was evaluated in a randomised, double-blind, placebo-controlled, 52-week study (PLUTO) in 93 paediatric patients with a clinical diagnosis of SLE according to the ACR classification criteria. Patients had active SLE disease, defined as a SELENA-SLEDAI score ≥6 and positive autoantibodies at screening as described in the adult trials. Patients were on a stable SLE treatment regimen (standard of care) and had similar inclusion criteria as the adult studies. Patients who had severe active lupus nephritis, severe active CNS lupus, primary immunodeficiency, IgA deficiency or acute or chronic infections requiring management were excluded from the study. The study was conducted in the US, South America, Europe, and Asia. Patient median age was 15 years (range 6 to 17 years). In the 5- to 11-year-old-group (n=13) the SELENA-SLEDAI score ranged from 4 to 13, and in 12- to 17-year-old-group (n=79) the SELENA-SLEDAI score ranged from 4 to 20. The majority (94.6%) of patients were female. The study was not powered for any statistical comparisons and all data are descriptive.
The primary efficacy endpoint was the SLE Responder Index (SRI) at Week 52 as described in the adult intravenous trials. There was a higher proportion of paediatric patients achieving an SRI response in patients receiving Benlysta compared with placebo. The response for the individual components of the endpoint were consistent with that of the SRI (Table 5). (See Table 5.)

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Among patients experiencing a severe flare, the median study day of the first severe flare was Day 159.5 in the Benlysta group and Day 82 in the placebo group. Severe flares were observed in 22.6% of the Benlysta group compared to 42.5% of the placebo group over the 52 weeks of observation (observed treatment difference = 19.9%; hazard ratio = 0.38, 95% CI: 0.18, 0.82). This was consistent with the findings from the adult intravenous clinical trials.
Using the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) Juvenile SLE Response Evaluation Criteria, a higher proportion of paediatric patients receiving Benlysta demonstrated improvement compared with placebo (Table 6). (See Table 6.)

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Solution for injection: The European Medicines Agency has deferred the obligation to submit the results of studies with Benlysta in one or more subsets of the paediatric population in SLE (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Transitioning from intravenous to subcutaneous administration: SLE patients transitioning from 10 mg/kg intravenously every 4 weeks to 200 mg subcutaneously weekly using a 1 to 4 week switching interval had pre-dose belimumab serum concentrations at their first subcutaneous dose close to their eventual subcutaneous steady-state trough concentration (see Dosage & Administration).
Based on simulations with population PK parameters the steady-state average belimumab concentrations for 200 mg subcutaneous every week were similar to 10 mg/kg intravenous every 4 weeks.
Powder for concentrate for solution for infusion: The intravenous pharmacokinetic parameters quoted as follows are based on population parameter estimates for the 563 patients who received Benlysta 10 mg/kg in the two Phase III studies.
Absorption: Benlysta is administered by intravenous infusion. Maximum serum concentrations of belimumab were generally observed at, or shortly after, the end of the infusion. The maximum serum concentration was 313 μg/ml (range: 173-573 μg/ml) based on simulating the concentration time profile using the typical parameter values of the population pharmacokinetic model.
Distribution: Belimumab was distributed to tissues with steady-state volume (Vss) of distribution of approximately 5 litres.
Biotransformation: Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.
Elimination: Serum belimumab concentrations declined in a bi-exponential manner, with a distribution half-life of 1.75 days and terminal half-life 19.4 days. The systemic clearance was 215 ml/day (range: 69-622 ml/day).
Special patient populations: Paediatric population: The pharmacokinetic parameters are based on individual parameter estimates from a population pharmacokinetic analysis of 53 patients from a study in paediatric patients. Following intravenous administration of 10 mg/kg on Days 0, 14 and 28, and at 4-week intervals thereafter, belimumab exposures were similar between paediatric and adult SLE subjects. Steady-state geometric mean Cmax, Cmin, and AUC values were 305 μg/mL, 42 μg/mL, and 2569 day·μg/mL in the 5- to 11-year-old-group, and 317 μg/mL, 52 μg/mL, and 3126 day·μg/mL in the 12- to 17-year-old-group (n=43).
Elderly: Benlysta has been studied in a limited number of elderly patients. Within the overall SLE intravenous study population, age did not affect belimumab exposure in the population pharmacokinetic analysis. However, given the small number of subjects ≥65 years, an effect of age cannot be ruled out conclusively.
Renal impairment: No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. During clinical development Benlysta was studied in patients with SLE and renal impairment (261 subjects with moderate renal impairment, creatinine clearance ≥30 and <60 ml/min; 14 subjects with severe renal impairment, creatinine clearance ≥15 and <30 ml/min). The reduction in systemic clearance estimated by population PK modelling for patients at the midpoints of the renal impairment categories relative to patients with median creatinine clearance in the PK population (79.9 ml/min) were 1.4% for mild (75 ml/min), 11.7% for moderate (45 ml/min) and 24.0% for severe (22.5 ml/min) renal impairment. Although proteinuria (≥ 2 g/day) increased belimumab clearance and decreases in creatinine clearance decreased belimumab clearance, these effects were within the expected range of variability. Therefore, no dose adjustment is recommended for patients with renal impairment.
Hepatic impairment: No specific studies have been conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue and changes in hepatic function are unlikely to have any effect on the elimination of belimumab.
Body weight/Body Mass Index (BMI): Weight-normalised belimumab dosing leads to decreased exposure for underweight subjects (BMI <18.5) and to increased exposure for obese subjects (BMI ≥30). BMI-dependent changes in exposure did not lead to corresponding changes in efficacy. Increased exposure for obese subjects receiving 10 mg/kg belimumab did not lead to an overall increase in AE rates or serious AEs compared to obese subjects receiving placebo. However, higher rates of nausea, vomiting and diarrhoea were observed in obese patients. None of these gastrointestinal events in obese patients were serious.
No dose adjustment is recommended for underweight or obese subjects.
Solution for injection: The subcutaneous pharmacokinetic parameters as follows are based on population parameter estimates from 661 subjects, comprised of 554 SLE patients and 107 healthy subjects, who received Benlysta subcutaneously.
Absorption: Benlysta in pre-filled pen is administered by subcutaneous injection.
Following subcutaneous administration the bioavailability of belimumab was approximately 74%. Steady-state exposure was reached after approximately 11 weeks of subcutaneous administration. The maximum serum concentration (Cmax) of belimumab at steady state was 108 μg/ml.
Distribution: Belimumab was distributed to tissues with steady-state volume (Vss) of distribution of approximately 5 litres.
Biotransformation: Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.
Elimination: Following subcutaneous administration, belimumab had a terminal half-life of 18.3 days. The systemic clearance was 204 ml/day.
Special Patient Populations: Paediatric population: No pharmacokinetic data are available in paediatric patients.
Elderly: Benlysta has been studied in a limited number of elderly patients. Age did not affect belimumab exposure in the subcutaneous population pharmacokinetic analysis. However, given the small number of subjects ≥65, an effect of age cannot be ruled out conclusively.
Renal impairment: No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. During clinical development, Benlysta was studied in a limited number of SLE patients with mild (creatinine clearance [CrCl] ≥60 and <90 ml/min), moderate (CrCl ≥30 and <60 ml/min), or severe (CrCl ≥15 and <30 ml/min) renal impairment: 121 patients with mild renal impairment and 30 patients with moderate renal impairment received Benlysta subcutaneously; 770 patients with mild renal impairment, 261 patients with moderate renal impairment and 14 patients with severe renal impairment received Benlysta intravenously.
No clinically significant reduction in systemic clearance as a result of renal impairment was observed. Therefore, no dose adjustment is recommended for patients with renal impairment.
Hepatic impairment: No specific studies have been conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue and changes in hepatic function are unlikely to have any effect on the elimination of belimumab.
Body weight/Body mass index (BMI): The effects of body weight and BMI on belimumab exposure after subcutaneous administration were not considered clinically meaningful. There was no significant impact on efficacy and safety based on weight. Therefore, no dose adjustment is recommended.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity and toxicity to reproduction.
Intravenous and subcutaneous administration to monkeys resulted in the expected reduction in the number of peripheral and lymphoid tissue B cell counts with no associated toxicological findings.
Reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab 150 mg/kg by intravenous infusion (approximately 9 times the anticipated maximum human clinical exposure) every 2 weeks for up to 21 weeks, and belimumab treatment was not associated with direct or indirect harmful effects with respect to maternal toxicity, developmental toxicity, or teratogenicity.
Treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of life in infant monkeys; IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
Effects on male and female fertility in monkeys were assessed in the 6-month repeat dose toxicology studies of belimumab at doses up to and including 50 mg/kg. No treatment-related changes were noted in the male and female reproductive organs of sexually mature animals. An informal assessment of menstrual cycling in females demonstrated no belimumab-related changes.
As belimumab is a monoclonal antibody no genotoxicity studies have been conducted. No carcinogenicity studies or fertility studies (male or female) have been performed.
Indications/Uses
Powder for concentrate for solution for infusion: Benlysta is indicated as add-on therapy in adult patients and patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti-dsDNA and low complement) despite standard therapy (see Pharmacology: Pharmacodynamics under Actions).
Solution for injection: Benlysta is indicated as add-on therapy in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti-dsDNA and low complement) despite standard therapy (see Pharmacology: Pharmacodynamics under Actions).
Dosage/Direction for Use
Powder for concentrate for solution for infusion: Benlysta treatment should be initiated and supervised by a qualified physician experienced in the diagnosis and treatment of SLE. Benlysta infusions should be administered by a qualified healthcare professional trained to give infusion therapy.
Administration of Benlysta may result in severe or life-threatening hypersensitivity reactions and infusion reactions. Patients have been reported to develop symptoms of acute hypersensitivity several hours after the infusion has been administered. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see Precautions and Adverse Reactions). Therefore, Benlysta should be administered in an environment where resources for managing such reactions are immediately available. Patients should remain under clinical supervision for a prolonged period of time (for several hours), following at least the first 2 infusions, taking into account the possibility of a late onset reaction.
Patients treated with Benlysta should be made aware of the potential risk of severe or life-threatening hypersensitivity and the potential for delayed onset or recurrence of symptoms. The package leaflet should be provided to the patient each time Benlysta is administered (see Precautions).
Posology: Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta (see Precautions).
The recommended dose regimen is 10 mg/kg Benlysta on Days 0, 14 and 28, and at 4-week intervals thereafter. The patient's condition should be evaluated continuously. Discontinuation of treatment with Benlysta should be considered if there is no improvement in disease control after 6 months of treatment.
Solution for injection: Benlysta treatment should be initiated and supervised by a qualified physician experienced in the diagnosis and treatment of SLE. It is recommended that the first subcutaneous injection of Benlysta should be under the supervision of a healthcare professional in a setting that is sufficiently qualified to manage hypersensitivity reactions, if necessary. The healthcare professional must provide proper training in subcutaneous technique and education about signs and symptoms of hypersensitivity reactions (see Precautions). A patient may self-inject or the patient caregiver may administer Benlysta after the healthcare professional determines that it is appropriate.
Posology: The recommended dose is 200 mg once weekly, administered subcutaneously. Dosing is not based on weight (see Pharmacology: Pharmacokinetics under Actions).
The patient's condition should be evaluated continuously. Discontinuation of treatment with Benlysta should be considered if there is no improvement in disease control after 6 months of treatment.
If a dose is missed, it should be administered as soon as possible. Thereafter, patients can resume dosing on their usual day of administration, or start a new weekly schedule from the day that the missed dose was administered. It is not necessary to administer two doses on the same day.
If patients wish to change their weekly dosing day, a new dose can be given on the newly preferred day of the week. Thereafter the patient should continue with the new weekly schedule from that day, even if the dosing interval may be temporarily less than a week.
Transition from intravenous to subcutaneous administration: If a patient is being transitioned from Benlysta intravenous administration to subcutaneous administration, the first subcutaneous injection should be administered 1 to 4 weeks after the last intravenous dose (see Pharmacology: Pharmacokinetics under Actions).
Special populations: Elderly: Powder for concentrate for solution for infusion: The efficacy and safety of Benlysta in the elderly has not been established. Data on patients ≥65 years are limited to <1.8% of the studied population. Therefore, the use of Benlysta in elderly patients is not recommended unless the benefits are expected to outweigh the risks. In case administration of Benlysta to elderly patients is deemed necessary, dose adjustment is not required (see Pharmacology: Pharmacokinetics under Actions).
Solution for injection: The efficacy and safety of Benlysta in the elderly has not been established. Data on patients ≥65 years are limited to <1.8% of the studied population. Therefore, the use of Benlysta in elderly patients is not recommended unless the benefits are expected to outweigh the risks. In case administration of Benlysta to elderly patients is deemed necessary, dose adjustment is not required (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: Belimumab has been studied in a limited number of SLE patients with renal impairment.
On the basis of the available information, dose adjustment is not required in patients with mild, moderate or severe renal impairment. Caution is however recommended in patients with severe renal impairment due to the lack of data (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No specific studies with Benlysta have been conducted in patients with hepatic impairment. Patients with hepatic impairment are unlikely to require dose adjustment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: Powder for concentrate for solution for infusion: The recommended dose regimen for children aged 5 years and older is 10 mg/kg Benlysta on Days 0, 14 and 28, and at 4-week intervals thereafter. The safety and efficacy of Benlysta in children aged below 5 years has not been established. No data are available.
Solution for injection: The safety and efficacy of Benlysta in children and adolescents (< 18 years of age) has not been established. No data are available.
Method of administration: Powder for concentrate for solution for infusion: Benlysta is administered intravenously by infusion, and must be reconstituted and diluted before administration. For instructions on reconstitution, dilution, and storage of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.
Benlysta should be infused over a 1-hour period.
Benlysta must not be administered as an intravenous bolus.
The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion must be discontinued immediately if the patient experiences a potentially life-threatening adverse reaction (see Precautions and Adverse Reactions).
Solution for injection: The pre-filled pen should be used for subcutaneous injection only. The recommended injection sites are the abdomen or thigh. When injecting in the same region, patients should be advised to use a different injection site each week; injections should never be given into areas where the skin is tender, bruised, red, or hard.
Comprehensive instructions for subcutaneous administration of Benlysta in a pre-filled pen are provided at the end of the package leaflet (see Step-by-step instructions).
Overdosage
There is limited clinical experience with overdose of Benlysta. Adverse reactions reported in association with cases of overdose have been consistent with those expected for belimumab.
Two doses up to 20 mg/kg administered 21 days apart by intravenous infusion have been given to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.
In the case of inadvertent overdose, patients should be carefully observed and supportive care administered, as appropriate.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Special Precautions
Benlysta has not been studied in the following adult and paediatric patient groups, and is not recommended in: severe active central nervous system lupus; severe active lupus nephritis (see Pharmacology: Pharmacodynamics under Actions); HIV; a history of, or current, hepatitis B or C; hypogammaglobulinaemia (IgG <400 mg/dl) or IgA deficiency (IgA <10 mg/dl); a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant.
Concomitant use with B cell targeted therapy or cyclophosphamide: Benlysta has not been studied in combination with other B cell targeted therapy or intravenous cyclophosphamide. Caution should be exercised if Benlysta is co-administered with other B cell targeted therapy or cyclophosphamide.
Infections: The mechanism of action of belimumab could increase the risk for the development of infections in adults and children with lupus, including opportunistic infections, and younger children may be at increased risk. Severe infections, including fatal cases, have been reported in SLE patients receiving immunosuppressant therapy, including belimumab (see Adverse Reactions). Physicians should exercise caution when considering the use of Benlysta in patients with severe or chronic infections or a history of recurrent infection. Patients who develop an infection while undergoing treatment with Benlysta should be monitored closely and careful consideration given to interrupting immunosuppressant therapy including belimumab until the infection is resolved. The risk of using Benlysta in patients with active or latent tuberculosis is unknown.
Depression and suicidality: In controlled clinical intravenous and subcutaneous studies, psychiatric disorders (depression, suicidal ideation and behaviour including suicides) have been reported more frequently in patients receiving Benlysta (see Adverse Reactions). Physicians should assess the risk of depression and suicide considering the patient's medical history and current psychiatric status before treatment with Benlysta and continue to monitor patients during treatment. Physicians should advise patients (and caregivers where appropriate) to contact their health care provider about new or worsening psychiatric symptoms. In patients who experience such symptoms, treatment discontinuation should be considered.
Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) has been reported with Benlysta treatment for SLE. Physicians should be particularly alert to symptoms suggestive of PML that patients may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriate diagnostic measures for PML should be considered. If PML is suspected, further dosing must be suspended until PML has been excluded.
Immunisation: Live vaccines should not be given for 30 days before, or concurrently with Benlysta, as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Benlysta.
Because of its mechanism of action, belimumab may interfere with the response to immunisations. However, in a small study evaluating the response to a 23-valent pneumococcal vaccine, overall immune responses to the different serotypes were similar in SLE patients receiving Benlysta compared with those receiving standard immunosuppressive treatment at the time of vaccination. There are insufficient data to draw conclusions regarding response to other vaccines.
Limited data suggest that Benlysta does not significantly affect the ability to maintain a protective immune response to immunisations received prior to administration of Benlysta. In a substudy, a small group of patients who had previously received either tetanus, pneumococcal or influenza vaccinations were found to maintain protective titres after treatment with Benlysta.
Malignancies and lymphoproliferative disorders: Immunomodulatory medicinal products, including Benlysta, may increase the risk of malignancy. Caution should be exercised when considering Benlysta therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy. Patients with malignant neoplasm within the last 5 years have not been studied, with the exception of those with basal or squamous cell cancers of the skin, or cancer of the uterine cervix, that has been fully excised or adequately treated.
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. No detrimental effects on such activities are predicted from the pharmacology of belimumab. The clinical status of the subject and the adverse reaction profile of Benlysta should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.
Powder for concentrate for solution for infusion: Traceability: In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.
Infusion reactions and hypersensitivity: Administration of Benlysta may result in hypersensitivity reactions and infusion reactions which can be severe, and fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see Dosage & Administration). The risk of hypersensitivity reactions is greatest with the first two infusions; however the risk should be considered for every infusion administered. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.
Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta. There is insufficient knowledge to determine whether premedication could diminish the frequency or severity of infusion reactions.
In clinical studies, serious infusion and hypersensitivity reactions affected approximately 0.9% of adult patients, and included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Infusion reactions occurred more frequently during the first two infusions and tended to decrease with subsequent infusions (see Adverse Reactions). Patients have been reported to develop symptoms of acute hypersensitivity several hours after the infusion has been administered. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see Dosage & Administration and Adverse Reactions). Therefore, Benlysta should be administered in an environment where resources for managing such reactions are immediately available. Patients should remain under clinical supervision for a prolonged period of time (for several hours), following at least the first 2 infusions, taking into account the possibility of a late onset reaction. Patients should be advised that hypersensitivity reactions are possible on the day of, or the day after infusion, and be informed of potential signs and symptoms and the possibility of recurrence. Patients should be instructed to seek immediate medical attention if they experience any of these symptoms. The package leaflet should be provided to the patient each time Benlysta is administered (see Dosage & Administration).
Delayed-type, non-acute hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema.
Solution for injection: Hypersensitivity: Administration of subcutaneous or intravenous Benlysta may result in hypersensitivity reactions which can be severe, and fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see Dosage & Administration). The risk of hypersensitivity reactions is greatest with the first two doses; however the risk should be considered for every administration. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see Dosage & Administration and Adverse Reactions).
Patients should be advised that hypersensitivity reactions are possible, on the day of, or several days after administration, and be informed of potential signs and symptoms and the possibility of recurrence. Patients should be instructed to seek immediate medical attention if they experience any of these symptoms. The package leaflet should be provided to the patient. Delayed-type, non-acute hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema.
In intravenous clinical studies, serious infusion and hypersensitivity reactions included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Please refer to the Summary of Product Characteristics for Benlysta powder for concentrate for solution for infusion (Precautions).
Use In Pregnancy & Lactation
Women of childbearing potential/Contraception in males and females: Women of childbearing potential must use effective contraception during Benlysta treatment and for at least 4 months after the last treatment.
Pregnancy: There are a limited amount of data from the use of Benlysta in pregnant women. No formal studies have been conducted. Besides an expected pharmacological effect i.e. reduction of B cells, animal studies in monkeys do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Benlysta should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.
Breast-feeding: It is unknown whether Benlysta is excreted in human milk or is absorbed systemically after ingestion. However, belimumab was detected in the milk from female monkeys administered 150 mg/kg every 2 weeks.
Because maternal antibodies (IgG) are excreted in breast milk, it is recommended that a decision should be made whether to discontinue breast-feeding or to discontinue Benlysta therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: There are no data on the effects of belimumab on human fertility. Effects on male and female fertility have not been formally evaluated in animal studies (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Adverse Reactions
Summary of the safety profile in adults: Powder for concentrate for solution for infusion 120 mg: The safety of belimumab in patients with SLE has been evaluated in 3 placebo-controlled studies. The data described as follows reflect exposure to Benlysta 10 mg/kg in 674 patients with SLE, including 472 exposed for at least 52 weeks. The safety data presented include data beyond Week 52 in some patients. Data from postmarketing reports are also included.
Patients received Benlysta 10 mg/kg intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 52 weeks.
The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti-malarials, non-steroidal anti-inflammatory medicinal products.
Adverse reactions were reported in 93% of Benlysta-treated patients and 92% of placebo-treated patients. The most frequently reported adverse reactions (≥10% of patient with SLE treated with Benlysta plus standard of care and at a rate ≥1% greater than placebo) were nausea, diarrhoea, and pyrexia. The proportion of patients who discontinued treatment due to adverse reactions was 7% for both Benlysta-treated and placebo-treated patients.
Powder for concentrate for solution for infusion 400 mg & Solution for injection: The safety of belimumab in patients with SLE has been evaluated in 3 pre-registration placebo-controlled intravenous studies, 1 placebo-controlled subcutaneous study, and one post-marketing, placebo-controlled intravenous study.
The data presented in the following table reflect exposure to Benlysta administered (10 mg/kg intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for up to 52 weeks) in 674 patients with SLE, including 472 exposed for at least 52 weeks, and 556 patients exposed to 200 mg Benlysta subcutaneously once weekly for up to 52 weeks. The safety data presented include data beyond Week 52 in some patients. Data from post-marketing reports are also included.
The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti-malarials, non-steroidal anti-inflammatory medicinal products.
Adverse reactions were reported in 87% of Benlysta-treated patients and 90% of placebo-treated patients. The most frequently reported adverse reactions (≥5% of patients with SLE treated with Benlysta plus standard of care and at a rate ≥1% greater than placebo) were viral upper respiratory tract infections, bronchitis, and diarrhoea. The proportion of patients who discontinued treatment due to adverse reactions was 7% for Benlysta-treated patients and 8% for placebo-treated patients.
Tabulated list of adverse reactions: Powder for concentrate for solution for infusion 120 mg: Adverse reactions are listed as follows by MedDRA system organ class and by frequency. The frequency categories used are: Very common ≥1/10, Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1000.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 7.)

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Powder for concentrate for solution for infusion 400 mg & Solution for injection: Adverse reactions are listed as follows by MedDRA system organ class and by frequency. The frequency categories used are: Very common ≥1/10, Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1000.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The frequency given is the highest seen with either formulation. (See Table 8.)

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Description of selected adverse reactions: Powder for concentrate for solution for infusion 120 mg: Infusion reactions and hypersensitivity: The incidence of infusion reactions and hypersensitivity reactions occurring during or on the same day as an infusion was 17% in the group receiving Benlysta and 15% in the group receiving placebo, with 1% and 0.3%, respectively, requiring permanent treatment discontinuation. These reactions were generally observed on the day of infusion, but acute hypersensitivity reactions may also occur on the day after dosing. Patients with a history of multiple drug allergies or significant hypersensitivity reactions may be at increased risk.
Infections: The overall incidence of infections was 70% in the group receiving Benlysta and 67% in the group receiving placebo. Infections occurring in at least 3% of Benlysta patients and at least 1% more frequently than patients receiving placebo were nasopharyngitis, bronchitis, pharyngitis, cystitis, and gastroenteritis viral. Serious infections occurred in 5% of patients receiving Benlysta or placebo. Infections leading to discontinuation of treatment occurred in 0.6% of patients receiving Benlysta and 1% of patients receiving placebo. Opportunistic infections have been reported in patients treated with Benlysta. Some infections were severe or fatal.
Leucopenia: The incidence of leucopenia reported as an adverse event was 4% in the group receiving Benlysta and 2% in the group receiving placebo.
Psychiatric disorders: Insomnia occurred in 7% of the group receiving Benlysta and 5% of the group receiving placebo. Depression was reported in 5% and 4% of the groups receiving Benlysta and placebo, respectively.
Gastrointestinal disorders: Obese patients [Body mass index (BMI) >30 kg/m2] treated with Benlysta reported higher rates of nausea, vomiting and diarrhoea relative to placebo, and compared with normal-weight patients (BMI ≥18.5 to ≤30 kg/m2). None of these gastrointestinal events in obese patients were serious.
Powder for concentrate for solution for infusion 400 mg: Data presented as follows are pooled from the intravenous clinical studies (10 mg/kg intravenous dose only) and the subcutaneous clinical study. Psychiatric disorders also includes data from a post-marketing study.
Infusion or injection-related systemic reactions and hypersensitivity: Infusion or injection-related systemic reactions and hypersensitivity were generally observed on the day of administration, but acute hypersensitivity reactions may also occur several days after dosing. Patients with a history of multiple drug allergies or significant hypersensitivity reactions may be at increased risk.
The incidence of infusion reactions and hypersensitivity reactions after intravenous administration occurring within 3 days of an infusion was 12% in the group receiving Benlysta and 10% in the group receiving placebo, with 1.2% and 0.3%, respectively, requiring permanent treatment discontinuation.
Infections: The overall incidence of infections in intravenous and subcutaneous studies was 63% in both groups receiving Benlysta or placebo. Infections occurring in at least 3% of patients receiving Benlysta and at least 1% more frequently than patients receiving placebo were viral upper respiratory tract infection, bronchitis and urinary tract infection bacterial. Serious infections occurred in 5% of patients in both groups receiving Benlysta or placebo; serious opportunistic infections accounted for 0.4% and 0% of these, respectively. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving Benlysta and 1.5% of patients receiving placebo. Some infections were severe or fatal.
For information on infections observed in paediatric patients see Paediatric population as follows.
Psychiatric disorders: In the pre-registration intravenous clinical studies, serious psychiatric events were reported in 1.2% (8/674) of patients receiving Benlysta 10 mg/kg and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.6% (4/674) of patients receiving Benlysta 10 mg/kg and 0.3% (2/675) of patients receiving placebo. There were two suicides in Benlysta-treated patients (including one receiving 1 mg/kg Benlysta).
In a randomised, double-blind, placebo-controlled, post-marketing study with Benlysta 10 mg/kg administered intravenously, serious psychiatric events were reported in 1.0% (20/2002) of patients receiving Benlysta and 0.3% (6/2001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2002) of patients receiving Benlysta and <0.1% (1/2001) of patients receiving placebo. The overall incidence of serious suicidal ideation or behaviour or self-injury without suicidal intent was 0.7% (15/2002) in patients receiving Benlysta and 0.2% (5/2001) in the placebo group. No suicide was reported in either group.
The intravenous studies did not exclude patients with a history of psychiatric disorders.
In the subcutaneous clinical study, which excluded patients with a history of psychiatric disorders, serious psychiatric events were reported in 0.2% (1/556) of patients receiving Benlysta and in no patients receiving placebo. There were no serious depression-related events or suicides reported in either group.
Leucopenia: The incidence of leucopenia reported as an adverse event was 3% in the group receiving Benlysta and 2% in the group receiving placebo.
Gastrointestinal disorders: Obese patients [Body mass index (BMI) >30 kg/m2] treated with intravenously administered. Benlysta reported higher rates of nausea, vomiting and diarrhoea relative to placebo, and compared with normal-weight patients (BMI ≥18.5 to ≤30 kg/m2). None of these gastrointestinal events in obese patients were serious.
Solution for injection: Data presented as follows are pooled from the intravenous clinical studies (10 mg/kg intravenous dose only) and the subcutaneous clinical study. Psychiatric disorders also includes data from a post-marketing study.
Infusion or injection-related systemic reactions and hypersensitivity: Infusion or injection-related systemic reactions and hypersensitivity were generally observed on the day of administration, but acute hypersensitivity reactions may also occur several days after dosing. Patients with a history of multiple drug allergies or significant hypersensitivity reactions may be at increased risk.
The incidence of infusion reactions and hypersensitivity reactions after intravenous administration occurring within 3 days of an infusion was 12% in the group receiving Benlysta and 10% in the group receiving placebo, with 1.2% and 0.3%, respectively, requiring permanent treatment discontinuation.
The incidence of post-injection systemic reactions and hypersensitivity reactions occurring within 3 days of subcutaneous administration was 7% in the group receiving Benlysta and 9% in the group receiving placebo. Clinically significant hypersensitivity reactions associated with Benlysta administered subcutaneously and requiring permanent treatment discontinuation were reported in 0.2% of patients receiving Benlysta and in no patients receiving placebo.
Infections: The overall incidence of infections in intravenous and subcutaneous studies was 63% in both groups receiving Benlysta or placebo. Infections occurring in at least 3% of patients receiving Benlysta and at least 1% more frequently than patients receiving placebo were viral upper respiratory tract infection, bronchitis, and urinary tract infection bacterial. Serious infections occurred in 5% of patients in both groups receiving Benlysta or placebo; serious opportunistic infections accounted for 0.4% and 0% of these, respectively. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving Benlysta and 1.5% of patients receiving placebo. Some infections were severe or fatal.
Psychiatric disorders: In the pre-registration intravenous clinical studies, serious psychiatric events were reported in 1.2% (8/674) of patients receiving Benlysta 10 mg/kg and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.6% (4/674) of patients receiving Benlysta 10 mg/kg and 0.3% (2/675) of patients receiving placebo. There were two suicides in Benlysta treated patients (including one receiving 1mg/kg Benlysta).
In a randomised, double-blind, placebo-controlled, post-marketing study with Benlysta 10 mg/kg administered intravenously, serious psychiatric events were reported in 1.0% (20/2002) of patients receiving Benlysta and 0.3% (6/2001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2002) of patients receiving Benlysta and <0.1% (1/2001) of patients receiving placebo. The overall incidence of serious suicidal ideation or behaviour or self-injury without suicidal intent was 0.7% (15/2002) in patients receiving Benlysta and 0.2% (5/2001) in the placebo group. No suicide was reported in either group.
The intravenous studies did not exclude patients with a history of psychiatric disorders.
In the subcutaneous clinical study, which excluded patients with a history of psychiatric disorders, serious psychiatric events were reported in 0.2% (1/556) of patients receiving Benlysta and in no patients receiving placebo. There were no serious depression-related events or suicides reported in either group.
Leucopenia: The incidence of leucopenia reported as an adverse event was 3% in the group receiving Benlysta and 2% in the group receiving placebo.
Injection site reactions: In the subcutaneous trial, the frequency of injection site reactions was 6.1% (34/556) and 2.5% (7/280) for patients receiving Benlysta and placebo, respectively. These injection site reactions (most commonly pain, erythema, hematoma, pruritus and induration) were mild to moderate in severity. The majority did not necessitate drug discontinuation.
Paediatric population: Powder for concentrate for solution for infusion 400 mg: The adverse reaction profile in paediatric patients is based on 52-week safety data from a placebo-controlled study in which 53 patients (6 to 17 years of age) with SLE received Benlysta (10 mg/kg intravenously on Days 0, 14, 28, and then every 28 days, on a background of concomitant treatments). No new safety signals were observed in the paediatric population 12 years of age and above (n=43). Safety data in children younger than 12 years of age (n=10) are limited.
Infections: 5- to 11-year-old group: infections were reported in 8/10 patients receiving Benlysta and 3/3 patients receiving placebo, and serious infections were reported in 1/10 patients receiving Benlysta and 2/3 patients receiving placebo (see Precautions).
12- to 17-year-old group: infections were reported in 22/43 patients receiving Benlysta and 25/37 patients receiving placebo, and serious infections were reported in 3/43 patients receiving Benlysta and 3/37 patients receiving placebo. In the open-label extension phase there was one fatal infection in a patient receiving Benlysta.
Reporting of suspected adverse reactions: Powder for concentrate for solution for infusion: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Drug Interactions
No in vivo interaction studies have been performed. The formation of some CYP450 enzymes is suppressed by increased levels of certain cytokines during chronic inflammation. It is not known if belimumab could be an indirect modulator of such cytokines. A risk for indirect reduction of CYP activity by belimumab cannot be excluded. On initiation or discontinuation of belimumab, therapeutic monitoring should be considered for patients being treated with CYP substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g. warfarin).
Caution For Usage
Special precautions for disposal and other handling: Powder for concentrate for solution for infusion: Preparation of the solution for infusion: Reconstitution: Reconstitution and dilution must be carried out under aseptic conditions.
Allow 10-15 minutes for the vial to warm to room temperature (15°C - 25°C).
It is recommended that a 21-25 gauge needle be used when piercing the vial stopper for reconstitution and dilution.
The 120 mg and 400 mg single-use vial of belimumab is reconstituted with 1.5 ml and 4.8 ml of water for injections, respectively, to yield a final concentration of 80 mg/ml belimumab.
The stream of water for injections should be directed toward the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature (15°C - 25°C) during reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the water has been added, but it may take up to 30 minutes.
Protect the reconstituted solution from sunlight.
If a mechanical reconstitution device is used to reconstitute Benlysta it should not exceed 500 rpm and the vial should be swirled for no longer than 30 minutes.
Once reconstitution is completed, the solution should be opalescent and colorless to pale yellow and without particles. Small air bubbles, however, are expected and acceptable.
After reconstitution, a volume of 1.5 ml and 5 ml (corresponding to 120 mg and 400 mg belimumab, respectively) can be withdrawn from each vial.
Dilution: The reconstituted medicinal product is diluted to 250 ml with sodium chloride 9 mg/ml (0.9%) solution for injection.
5% glucose intravenous solutions are incompatible with Benlysta and must not be used.
From a 250 ml infusion bag or bottle of sodium chloride 9 mg/ml (0.9%) solution for injection, withdraw and discard a volume equal to the volume of the reconstituted Benlysta solution required for the patient's dose. Then add the required volume of the reconstituted Benlysta solution into the infusion bag or bottle. Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.
Inspect the Benlysta solution visually for particulate matter and discoloration prior to administration. Discard the solution if any particulate matter or discoloration is observed.
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
Method of administration: Benlysta is infused over a 1 hour period.
Benlysta should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Benlysta with other agents.
No incompatibilities between Benlysta and polyvinylchloride or polyolefin bags have been observed.
Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Solution for injection: Comprehensive instructions for subcutaneous administration of Benlysta in a pre-filled pen are provided as follows (see Step-by-step instructions).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Step-by-step instructions for using the pre-filled pen: Once-Weekly: Follow these instructions on how to use the pre-filled pen correctly. Failure to follow these instructions may affect proper function of the pre-filled pen. The patient should also receive training on how to use the pre-filled pen.
Benlysta is for use under the skin only (subcutaneous).
1. Gather and check supplies: Gather supplies: Remove one sealed tray containing a pre-filled pen from the refrigerator.
Find a comfortable, well-lit and clean surface and place the following supplies within reach: Benlysta pre-filled pen, alcohol swab (not included in the pack), gauze pad or cotton wool ball (not included in the pack), empty container with a tight-fitting lid for pen disposal (not included in the pack).
Do not perform the injection if the patient does not have all the supplies listed.
Check the expiry date: Peel back the film of the tray and remove the pre-filled pen.
Check the expiry date on the pre-filled pen.
Do not use if the expiry date has passed.
2. Prepare and inspect the pre-filled pen: Allow to come to room temperature: Leave the pen at room temperature for 30 minutes. Injecting cold Benlysta may take longer and may be uncomfortable.
Do not warm the pen in any other way. For example, do not warm it in a microwave oven, hot water or direct sunlight.
Do not remove the ring cap during this step.
Inspect the Benlysta solution: Look in the inspection window to check that the Benlysta solution is colourless to slightly yellow in colour.
It is normal to see one or more air bubbles in the solution.
Do not use if the solution looks cloudy, discoloured or has particles.
3. Choose and clean the injection site: Choose the injection site: Choose an injection site (abdomen or thigh).
Do not inject into the exact same site each time. This is to avoid the skin becoming hardened.
Do not inject in areas where the skin is tender, bruised, red or hard.
Do not inject within 5 cm (2 inches) of the navel (belly button).
Clean the injection site: Wash the hands.
Clean the injection site by wiping it with an alcohol swab. Allow the skin to air dry.
Do not touch this area again before giving the injection.
4. Prepare for the injection: Remove the ring cap.
Do not remove the ring cap until immediately before the injection.
Remove the ring cap by pulling or twisting it off. The ring cap may be twisted off either clockwise or anti-clockwise.
Do not put the ring cap back onto the pen.
Position the pen: Hold the pen comfortably so that the patient can view the inspection window. This is important so that the patient can confirm a complete dose.
If needed, firm the injection site by pulling or stretching the skin.
Position the pen straight over the injection site (at a 90° angle). Make sure the gold needle guard is flat on the skin.
5. Inject Benlysta: Start the injection: Firmly press the pen all the way down onto the injection site and hold in place.
This will insert the needle and start the injection.
The patient may hear a first "click" at the start of the injection. The patient will see the purple indicator start to move through the inspection window.
Complete the injection: Continue to hold the pen down until the purple indicator has stopped moving. The patient may hear a second "click" a few seconds before the purple indicator stops moving.
The injection may take up to 15 seconds to complete.
When the injection is complete, lift the pen from the injection site.
6. Dispose and inspect: Dispose of the used pen: Do not put the ring cap back onto the pen.
Dispose of the used pen and ring cap in an empty container with a tight-fitting lid.
Ask the doctor or pharmacist for instructions on how to properly dispose of a used pen or container of used pens.
Do not recycle or throw the used pen, or container of used pens, in household waste.
Inspect the injection site: There may be a small amount of blood at the injection site.
If needed, press a cotton ball or gauze pad on the injection site.
Do not rub the injection site.
Incompatibilities: Powder for concentrate for solution for infusion: Benlysta is not compatible with 5% glucose.
This medicinal product must not be mixed with other medicinal products except those previously mentioned in Special precautions for disposal and other handling.
Solution for injection: None known.
Storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see Shelf life as follows.
Shelf life: Powder for concentrate for solution for infusion: Reconstituted solution: After reconstitution with water for injections, the reconstituted solution, if not used immediately, should be protected from direct sunlight, and stored refrigerated at 2°C - 8°C.
Reconstituted and diluted solution for infusion: Solution of Benlysta diluted in sodium chloride 9 mg/ml (0.9%) solution for injection may be stored at 2°C - 8°C or room temperature (15°C - 25°C).
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
MIMS Class
ATC Classification
L04AA26 - belimumab ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
Presentation/Packing
Powd for concentrate for soln for infusion (vial) (white to off-white) 120 mg x 1's. 400 mg x 1's. Soln for inj (pre-filled pen) 200 mg/mL (clear to opalescent, colourless to pale yellow, with a pH of 6) x 1's.
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