ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions have been observed with BENLYSTA and are discussed in detail in the Warnings and Precautions section:oSerious Infections [see Warnings and Precautions (5.1)]oHypersensitivity Reactions, including Anaphylaxis [see Warnings and Precautions (5.2)]oInfusion Reactions [see Warnings and Precautions (5.3)]oDepression and Suicidality [see Warnings and Precautions (5.4)]oMalignancy [see Warnings and Precautions (5.5)]Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.. oSerious Infections [see Warnings and Precautions (5.1)]. oHypersensitivity Reactions, including Anaphylaxis [see Warnings and Precautions (5.2)]. oInfusion Reactions [see Warnings and Precautions (5.3)]. oDepression and Suicidality [see Warnings and Precautions (5.4)]. oMalignancy [see Warnings and Precautions (5.5)]. oCommon adverse reactions in adults (>=5%): nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, pharyngitis, and injection site reactions (subcutaneous administration). (6.1)oAdverse reactions in pediatric patients aged years and older were consistent with those observed in adults. (6.2)To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-877-423-6597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oCommon adverse reactions in adults (>=5%): nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, pharyngitis, and injection site reactions (subcutaneous administration). (6.1). oAdverse reactions in pediatric patients aged years and older were consistent with those observed in adults. (6.2). 6.1 Clinical Trials Experience with Intravenous Administration. AdultsThe data described in Table reflect exposure to BENLYSTA administered intravenously plus standard therapy compared with placebo plus standard therapy in 2,133 adult patients with SLE in controlled trials (Trials 1, 2, and 3). Patients received BENLYSTA plus standard therapy at doses of mg/kg (n 673), mg/kg (n 111; Trial only), or 10 mg/kg (n 674), or placebo plus standard therapy (n 675) intravenously over 1-hour period on Days 0, 14, 28, and then every 28 days. In of the trials (Trial and Trial 3), treatment was given for 48 weeks, while in the other trial (Trial 2) treatment was given for 72 weeks [see Clinical Studies (14.1)]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the intravenous doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended intravenous dose of 10 mg/kg compared with placebo.The population had mean age of 39 years (range: 18 to 75), 94% were female, and 52% were White. In these trials, 93% of patients treated with BENLYSTA plus standard therapy reported an adverse event compared with 92% treated with placebo plus standard therapy.The most common serious adverse events were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo plus standard therapy, respectively), some of which were fatal [see Warnings and Precautions (5.1)].The most commonly reported adverse events, occurring in >=5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA plus standard therapy and 7.1% for patients receiving placebo plus standard therapy. The most common adverse reactions resulting in discontinuation of treatment (>=1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo).Table lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg plus standard therapy and at an incidence at least 1% greater than that observed with placebo plus standard therapy in controlled trials (Trials 1, 2, and 3).Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Adult Patients with SLE Treated with BENLYSTA 10 mg/kg plus Standard Therapy and at Least 1% More Frequently than in Patients Receiving Placebo plus Standard TherapyPreferred TermBENLYSTA 10 mg/kg Standard Therapy(n 674)%Placebo Standard Therapy(n 675)%Nausea1512Diarrhea129Pyrexia108Nasopharyngitis97Bronchitis95Insomnia75Pain in extremity64Depression54Migraine54Pharyngitis53Cystitis43Leukopenia42Gastroenteritis viral31Infections: In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, the overall incidence of infections was 71% in patients receiving BENLYSTA compared with 67% in patients receiving placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Serious infections occurred in 6.0% of patients receiving BENLYSTA and in 5.2% of patients receiving placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Fatal infections occurred in 0.3% (4/1,458) of patients receiving BENLYSTA and in 0.1% (1/675) of patients receiving placebo.In randomized, double-blind, placebo-controlled, 104-week trial of active lupus nephritis in adults receiving BENLYSTA administered intravenously (N 448), the overall incidence of infections was 82% in patients receiving BENLYSTA compared with 76% in patients receiving placebo. Serious infections occurred in 14% of patients receiving BENLYSTA and in 17% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving BENLYSTA and in 0.9% (2/224) of patients receiving placebo.In randomized, double-blind, placebo-controlled, 52-week, postmarketing safety trial of BENLYSTA administered intravenously in adults with SLE (N 4,003), the incidence of serious infections was 3.7% in patients receiving BENLYSTA compared with 4.1% in patients receiving placebo. Serious infections leading to discontinuation of treatment occurred in 1.0% of patients receiving BENLYSTA and in 0.9% of patients receiving placebo. Fatal infections occurred in 0.45% (9/2,002) of patients receiving BENLYSTA and in 0.15% (3/2,001) of patients receiving placebo, where the incidence of all-cause mortality was 0.50% (10/2,002) in patients receiving BENLYSTA and 0.40% (8/2,001) in patients receiving placebo.Depression and Suicidality: In controlled clinical trials of BENLYSTA administered intravenously in adults with SLE (N 2,133), psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), primarily related to depression-related events (6.3% BENLYSTA; 4.7% placebo), insomnia (6.0% BENLYSTA; 5.3% placebo), and anxiety (3.9% BENLYSTA; 2.8% placebo). Serious psychiatric events were reported in 0.8% (12/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.4% (6/1,458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA (one with 10 mg/kg and one with mg/kg).In randomized, double-blind, placebo-controlled, 52-week, postmarketing safety trial of BENLYSTA administered intravenously in adults with SLE (N 4,003), serious psychiatric events were reported in 1.0% (20/2,002) of patients receiving BENLYSTA and 0.3% (6/2,001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2,002) of patients receiving BENLYSTA and in <0.1% (1/2,001) receiving placebo. The overall incidence of serious suicidal ideation or behavior or self-injury without suicidal intent was 0.7% (15/2,002) of patients receiving BENLYSTA and 0.2% (5/2,001) of patients receiving placebo. On the Columbia-Suicide Severity Rating Scale (C-SSRS), 2.4% (48/1,974) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 2.0% (39/1,988) of patients receiving placebo. No suicide was reported in either group.The intravenous trials above did not exclude patients with history of psychiatric disorders.Black/African-American Patients: The safety of BENLYSTA 10 mg/kg administered intravenously plus standard therapy (n 331) compared with placebo plus standard therapy (n 165) in Black patients with SLE (Trial 4) was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in the overall population [see Clinical Studies (14.1)].Lupus Nephritis: The safety of BENLYSTA 10 mg/kg administered intravenously plus standard therapy (n 224) compared with placebo plus standard therapy (n 224) was evaluated in adults with active lupus nephritis for up to 104 weeks (Trial 5) [see Clinical Studies (14.2)]. The adverse reactions observed were consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in patients with SLE. Cases of myelosuppression, including febrile neutropenia, leukopenia, and pancytopenia, were observed in subjects who received induction therapy with cyclophosphamide followed by maintenance therapy with azathioprine, or mycophenolate.Pediatric PatientsThe safety of BENLYSTA administered intravenously plus standard therapy (n 53) compared with placebo plus standard therapy (n 40) was evaluated in 93 pediatric patients with SLE (Trial 6). The adverse reactions observed were consistent with those observed in adults [see Clinical Studies (14.3)].. 6.2 Clinical Trials Experience with Subcutaneous Administration in Adults. The data described below reflect exposure to BENLYSTA administered subcutaneously plus standard therapy compared with placebo plus standard therapy in 836 patients with SLE in controlled trial (Trial 7). In addition to standard therapy, patients received BENLYSTA 200 mg (n 556) or placebo (n 280) (2:1 randomization) once weekly for up to 52 weeks [see Clinical Studies (14.4)].The overall population had mean age of 39 years (range: 18 to 77), 94% were female, and 60% were White. In the trial, 81% of patients treated with BENLYSTA plus standard therapy reported an adverse event compared with 84% treated with placebo plus standard therapy. The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trial was 7.2% of patients receiving BENLYSTA plus standard therapy and 8.9% of patients receiving placebo plus standard therapy.The safety profile observed for BENLYSTA administered subcutaneously plus standard therapy was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy, with the exception of local injection site reactions.InfectionsIn controlled trial of BENLYSTA administered subcutaneously in adults with SLE (N 836), the overall incidence of infections was 55% in patients receiving BENLYSTA compared with 57% in patients receiving placebo (serious infections: 4.1% with BENLYSTA and 5.4% with placebo). The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously. Fatal infections occurred in 0.5% (3/556) of patients receiving BENLYSTA and in no patients receiving placebo (0/280).Depression and SuicidalityIn controlled trial of BENLYSTA administered subcutaneously in adults with SLE (N 836), which excluded patients with history of psychiatric disorders, psychiatric events were reported in 6% of patients receiving BENLYSTA and 11% of patients receiving placebo. Depression-related events were reported in 2.7% (15/556) of patients receiving BENLYSTA and 3.6% (10/280) of patients receiving placebo. 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. On the C-SSRS, 1.3% (7/554) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 0.7% (2/277) of patients receiving placebo.Injection Site ReactionsIn controlled clinical trial of BENLYSTA administered subcutaneously in adults with SLE (N 836), the frequency of injection site reactions was 6.1% (34/556) for patients receiving BENLYSTA plus standard therapy and 2.5% (7/280) for patients receiving placebo plus standard therapy. These injection site reactions (most commonly pain, erythema, hematoma, pruritus, and induration) were mild to moderate in severity. The majority (94%) did not necessitate discontinuation of treatment.. 6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of BENLYSTA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.oFatal anaphylaxis [see Warnings and Precautions (5.2)].. oFatal anaphylaxis [see Warnings and Precautions (5.2)].. 6.4 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies in other studies or to other products may be misleading.In Trials and (intravenous dosing in adults with SLE), anti-belimumab antibodies were detected in of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in patients receiving BENLYSTA mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. In Trial (intravenous dosing in adult Black patients), anti-belimumab antibodies were detected in of 321 (0.6%) patients receiving BENLYSTA 10 mg/kg during the 52-week, placebo-controlled period. In Trial (intravenous dosing in adults with lupus nephritis), there was no formation of anti-belimumab antibodies in 224 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 104-week, placebo-controlled period. In Trial (intravenous dosing in pediatric patients with SLE), there was no formation of anti-belimumab antibodies in 53 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 52-week, placebo-controlled period. In Trial (subcutaneous dosing in adults with SLE), there was no formation of anti-belimumab antibodies in 556 patients receiving BENLYSTA 200 mg during the 52-week, placebo-controlled period.The clinical relevance of the presence of anti-belimumab antibodies is not known.The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. BENLYSTA is BLyS-specific inhibitor that blocks the binding of soluble BLyS, B-cell survival factor, to its receptors on cells. BENLYSTA does not bind cells directly, but by binding BLyS, BENLYSTA inhibits the survival of cells, including autoreactive cells, and reduces the differentiation of cells into immunoglobulin-producing plasma cells.. 12.2 Pharmacodynamics. Treatment with BENLYSTA in adult patients significantly reduced circulating CD19+, CD20+, naive, and activated cells, and the SLE B-cell subset at Week 52. Reductions in naive and the SLE B-cell subset were observed as early as Week and sustained to Week 52. Memory cells increased initially and slowly declined toward baseline levels by Week 52.Treatment with BENLYSTA in adult patients led to reductions in IgG and anti-double-stranded DNA antibodies (anti-dsDNA) which were observed as early as Week and sustained through Week 52. In patients with low complement levels at baseline, treatment led to increases in complement C3 and C4 as early as Week 12 and were sustained through Week 52.The pharmacodynamic response observed in Black patients (Trial 4) was consistent with the previous studies.In patients with active lupus nephritis (Trial 5), following treatment with BENLYSTA, there was decrease in serum IgG as early as Week 4, and subsequently there was an increase in serum IgG levels which was associated with decreased proteinuria. Reductions in autoantibodies, increases in complement, and reductions in circulating total cells and B-cell subsets observed were consistent with the SLE studies.In Trial (pediatric dosing), the pharmacodynamic response was consistent with the adult data.The clinical relevance of above mentioned pharmacodynamic biomarkers has not been established.. 12.3 Pharmacokinetics. Intravenous Infusion in AdultsSystemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table are based on population parameter estimates from 563 adult patients who received BENLYSTA 10 mg/kg. Table 2. Population Pharmacokinetic Parameters in Adult Patients with SLE after Intravenous Infusion of BENLYSTA 10 mg/kga Intravenous infusions were administered at 2-week intervals for the first doses and at 4-week intervals thereafter.Pharmacokinetic ParameterPopulation Estimates(n 563)Peak concentration (Cmax, mcg/mL)313Area under the curve (AUC0-, daymcg/mL)3,083Distribution half-life (t 1/2 days)1.8Terminal half-life (t 1/2 days)19.4Systemic clearance (CL, mL/day)215Volume of distribution (Vss, L)5Lupus Nephritis: population pharmacokinetic analysis was conducted in 224 adult patients with lupus nephritis who received belimumab 10 mg/kg intravenously (Days 0, 14, 28, and then every 28 days up to 104 weeks) plus standard therapy [see Clinical Studies (14.2)]. In patients with lupus nephritis, due to additional clearance associated with proteinuria, belimumab exposure was initially lower than observed in SLE studies and lower belimumab exposure was observed in patients with higher proteinuria. When the proteinuria was decreased to approximately <=1 g/g after treatment, belimumab clearance and exposure were similar to that observed in patients with SLE who received belimumab 10 mg/kg intravenously. The available data do not support dose adjustment in patients with high proteinuria.Subcutaneous Injection in AdultsSystemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table are based on population parameter estimates from 661 subjects after subcutaneous administration of belimumab 200 mg once weekly. The time to reach maximum serum concentration (Cmax) was 2.6 days (Tmax) after administration at steady state. The bioavailability of belimumab was approximately 74%. With weekly subcutaneous administration there were minor fluctuations around the average concentration (Cavg 104 mcg/mL), with Cmin (97 mcg/mL) being only slightly below Cavg.Table 3. Population Pharmacokinetic Parameters in Adults after Subcutaneous Administration of BENLYSTAPharmacokinetic ParameterPopulation Estimates(n 661)Peak concentration (Cmax, mcg/mL)108Area under the curve (AUC0-, daymcg/mL)726Distribution half-life (t 1/2 days)1.1Terminal half-life (t 1/2 days)18.3Systemic clearance (CL, mL/day)204Volume of distribution (Vss, L)5Lupus Nephritis: Based on population pharmacokinetic modeling and simulation of the subcutaneous 400-mg weekly loading dose, the average belimumab concentration during the first 12 weeks was predicted to be 78 mcg/mL, which is similar to the estimated concentration of 89 mcg/mL for intravenous administration. The loading dose of 400 mg weekly provides steady-state concentrations from Week of dosing. The steady-state average concentrations of subcutaneous administration of belimumab 200 mg once weekly in adults with lupus nephritis are predicted to be similar to those observed in adults with lupus nephritis receiving belimumab 10 mg/kg intravenously every weeks.Specific PopulationsThe following information is based on the population pharmacokinetic analyses of intravenous administration and subcutaneous administration of BENLYSTA.Age: Age did not significantly influence the pharmacokinetics of belimumab, where the majority of subjects were between 18 and 45 years (70% with intravenous dosing; 74% with subcutaneous dosing). Geriatric Patients: Limited pharmacokinetic data are available for elderly patients as less than 2% of the subjects included in the pharmacokinetic analysis were 65 years or older [see Use in Specific Populations (8.5)]. Pediatric Patients: The pharmacokinetic parameters are based on individual parameter estimates from population pharmacokinetic analysis of 53 pediatric patients (Trial 6). Following IV administration of 10 mg/kg on Days 0, 14, and 28, and at 4-week intervals thereafter, belimumab exposures were similar between pediatric and adult subjects with SLE. Steady-state geometric mean Cmax, Cmin, Cavg, and AUC values were 305, 42, 92 mcg/mL, and 2,569 daymcg/mL in the 5- to 11-year-old group, and 317, 52, 112 mcg/mL and 3,126 daymcg/mL in the 12- to 17-year-old group. [See Use in Specific Populations (8.4).] Male and Female Patients: Gender did not significantly influence belimumab pharmacokinetics in the largely female trial population (94% with intravenous dosing; 85% with subcutaneous dosing).Racial Groups: Race did not significantly influence belimumab pharmacokinetics. The racial distribution with intravenous administration was 53% White, 16% Asian, 16% Alaska native/American Indian, and 14% Black in Trials 1, 2, and 3. Trial enrolled only Black patients. The racial distribution with subcutaneous administration (Trial 7) was 61% White, 20% Asian, 11% Black, and 6% Alaska native/American Indian.Weight: Body weight and body mass index (BMI) had no clinically relevant effect on the pharmacokinetics of belimumab administered subcutaneously in adults. No dose adjustment is recommended based on weight or BMI for subcutaneous administration.Patients with Renal Impairment: No formal trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. BENLYSTA was studied in limited number of adult patients with SLE who had mild (CrCl >=60 and <90 mL/min), moderate (CrCl >=30 and <60 mL/min), or severe (CrCl >=15 and <30 mL/min) renal impairment: 770 patients with mild renal impairment, 261 patients with moderate renal impairment, and 14 patients with severe renal impairment received belimumab intravenously; 121 patients with mild renal impairment and 30 patients with moderate renal impairment received belimumab subcutaneously. [See Use in Specific Populations (8.6).] Patients with Hepatic Impairment: No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics. [See Use in Specific Populations (8.7).] Drug Interaction StudiesNo formal drug interaction studies have been conducted with BENLYSTA. Concomitant use of mycophenolate, cyclophosphamide, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and/or HMG-CoA reductase inhibitors did not significantly influence belimumab pharmacokinetics. Coadministration of steroids and angiotensin-converting enzyme (ACE) inhibitors resulted in an increase of systemic clearance of belimumab that was not clinically significant because the magnitude was well within the range of normal variability of clearance. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated.. Geriatric Patients: Limited pharmacokinetic data are available for elderly patients as less than 2% of the subjects included in the pharmacokinetic analysis were 65 years or older [see Use in Specific Populations (8.5)].. Pediatric Patients: The pharmacokinetic parameters are based on individual parameter estimates from population pharmacokinetic analysis of 53 pediatric patients (Trial 6). Following IV administration of 10 mg/kg on Days 0, 14, and 28, and at 4-week intervals thereafter, belimumab exposures were similar between pediatric and adult subjects with SLE. Steady-state geometric mean Cmax, Cmin, Cavg, and AUC values were 305, 42, 92 mcg/mL, and 2,569 daymcg/mL in the 5- to 11-year-old group, and 317, 52, 112 mcg/mL and 3,126 daymcg/mL in the 12- to 17-year-old group. [See Use in Specific Populations (8.4).].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and effectiveness of BENLYSTA administered intravenously plus standard therapy were evaluated in randomized, double-blind, placebo-controlled trials involving 2,581 adult patients with SLE (Trial 1, NCT 00071487, Trial 2, NCT 00410384, Trial 3, NCT 00424476, and Trial NCT 01632241), and one trial involving 93 pediatric patients (Trial 6, NCT 01649765) with SLE according to the American College of Rheumatology criteria. In these trials, patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were on stable standard therapy SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics and intravenous cyclophosphamide was not permitted.In addition, the safety and effectiveness of BENLYSTA administered intravenously plus standard therapy was evaluated in randomized, double-blind, placebo-controlled trial in 448 adult patients with active lupus nephritis (Trial 5; NCT 01639339).. 14.1Clinical Trials with Intravenous Administration in Adults with SLE Trial 1: SLE BENLYSTA mg/kg, mg/kg, 10 mg/kg IntravenousTrial enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg BENLYSTA plus standard therapy compared with placebo plus standard therapy over 52 weeks in patients with SLE. Patients had to have Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of >4 at baseline and history of autoantibodies (anti-nuclear antibody [ANA] and/or anti-double-stranded DNA [anti-dsDNA]), but 28% of the population was autoantibody negative at baseline. The co-primary endpoints were percent change in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No significant differences between any of the groups receiving BENLYSTA and the group receiving placebo were observed. Exploratory analysis of this trial identified subgroup of patients (72%) who were autoantibody positive in whom BENLYSTA appeared to offer benefit. The results of this trial informed the design of Trials and and led to the selection of target population and indication that is limited to autoantibody-positive SLE patients.Trials 2, and 4: SLE BENLYSTA mg/kg and 10 mg/kg IntravenousTrials and were randomized, double-blind, placebo-controlled trials in patients with SLE that were similar in design except duration Trial (N 819) was 76 weeks duration and Trial (N 865) was 52 weeks duration. Patients had active SLE disease with SELENA-SLEDAI score >=6 and positive autoantibody test results at screening. Patients were excluded from the trial if they had ever received treatment with B-cell-targeted agent or if they were currently receiving other biologic agents. Intravenous cyclophosphamide was not permitted within the previous months or during the trial. Trial was conducted primarily in North America and Europe. Trial was conducted in South America, Eastern Europe, Asia, and Australia.Baseline concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%), immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine, methotrexate, and mycophenolate), and antimalarials (Trial 2: 63%, Trial 3: 67%). Most patients (>70%) were receiving or more classes of SLE medications.In Trial and Trial 3, more than 50% of patients had or more active organ systems involved at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (82% in both trials), immune (Trial 2: 74%, Trial 3: 85%), and musculoskeletal (Trial 2: 73%, Trial 3: 59%). Less than 16% of patients had some degree of renal activity and less than 7% of patients had activity in the vascular, cardio-respiratory, or CNS systems.At screening, patients were stratified by disease severity based on their SELENA-SLEDAI score (<=9 vs. >=10), proteinuria level (<2 g/24 vs. >=2 g/24 h), and race (African or Indigenous-American descent vs. other), and then randomly assigned to receive BENLYSTA mg/kg, BENLYSTA 10 mg/kg, or placebo in addition to standard therapy. The patients were administered trial medication intravenously over 1-hour period on Days 0, 14, 28, and then every 28 days for 48 weeks in Trial and for 72 weeks in Trial 2.The primary efficacy endpoint was composite endpoint (SLE Responder Index-4 or SRI-4) that defined response as meeting each of the following criteria at Week 52 compared with baseline:o>=4-point reduction in the SELENA-SLEDAI score, andono new British Isles Lupus Assessment Group (BILAG) organ domain score or new BILAG organ domain scores, andono worsening (<0.30-point increase) in Physicians Global Assessment (PGA) score.The SRI uses the SELENA-SLEDAI score as an objective measure of reduction in global disease activity; the BILAG index to ensure no significant worsening in any specific organ system; and the PGA to ensure that improvements in disease activity are not accompanied by worsening of the patients condition overall.In both Trials and 3, the proportion of patients with SLE achieving an SRI-4 response, as defined for the primary endpoint, was significantly higher in the group receiving BENLYSTA 10 mg/kg plus standard therapy than in the group receiving placebo plus standard therapy. The effect on the SRI-4 was not consistently significantly different for patients receiving BENLYSTA mg/kg plus standard therapy relative to placebo plus standard therapy in both trials. The 1-mg/kg dose is not recommended. The trends in comparisons between the treatment groups for the rates of response for the individual components of the endpoint were generally consistent with that of the SRI-4 (Table 4). At Week 76 in Trial 2, the SRI-4 response rate with BENLYSTA 10 mg/kg was not significantly different from that of placebo (39% and 32%, respectively).Table 4. Clinical Response Rate in Patients with SLE after 52 Weeks of Treatmenta The 1-mg/kg dose is not recommended.b Patients dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. In both trials, higher proportion of placebo patients were considered as failures for this reason compared with the groups receiving BENLYSTA.Trial 2Trial 3ResponsePlacebo +Standard Therapy(n 275)BENLYSTA1 mg/kg Standard Therapya (n 271)BENLYSTA10 mg/kg Standard Therapy(n 273)Placebo +Standard Therapy(n 287)BENLYSTA1 mg/kg Standard Therapya (n 288)BENLYSTA10 mg/kg Standard Therapy(n 290)SLE Responder Index-4 (SRI-4)b 34%41% = 0.10443% = 0.02144%51% = 0.01358% <0.001Odds Ratio (95% CI) vs. placebo1.3 (0.9, 1.9)1.5 (1.1, 2.2)1.6 (1.1, 2.2)1.8 (1.3, 2.6)Components of SLE Responder Index-4 (SRI-4)Percent of patients with reduction in SELENA-SLEDAI >=436%43%47%46%53%58%Percent of patients with no worsening by BILAG index65%75%69%73%79%81%Percent of patients with no worsening by PGA63%73%69%69%79%80%The reduction in disease activity seen in the SRI-4 was related primarily to improvement in the most commonly involved organ systems; namely, mucocutaneous, musculoskeletal, and immune.Effect in Black/African-American Patients: In Trials and 3, exploratory sub-group analyses of SRI-4 response rate in Black patients (n 148) were performed. The SRI-4 response rate in Black patients in groups receiving BENLYSTA plus standard therapy was less than that in the group receiving placebo plus standard therapy (22/50 or 44% for placebo, 15/48 or 31% for BENLYSTA mg/kg, and 18/50 or 36% for BENLYSTA 10 mg/kg).Trial was 2:1 randomized, placebo-controlled trial in Black patients with SLE (N 448) conducted in North America, South America, Europe, and Africa (same study design as Trials and with exceptions of patients having baseline SELENA-SLEDAI score of >8 and using the modified SLEDAI-2K scoring for proteinuria). The population had mean age of 39 years (range: 18 to 71) and 97% were female. The proportion of Black patients achieving an SRI-S2K response at Week 52 (primary endpoint), and the individual components of the endpoint, were higher in the group receiving BENLYSTA 10 mg/kg plus standard therapy relative to the group receiving placebo plus standard therapy. However, the treatment difference was not statistically significant (Table 5).Table 5. Clinical Response Rate in Black Patients with SLE after 52 Weeks of Treatment (Trial 4)a Patients dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. higher proportion of patients receiving placebo were considered as failures for this reason compared with the group receiving BENLYSTA.ResponsePlacebo +Standard Therapy(n 149) BENLYSTA10 mg/kg +Standard Therapy(n 299) SLE Responder Index (SRI-S2K)a 42%49%Odds Ratio (95% CI)1.4 (0.9, 2.1)P 0.107Components of SLE Responder Index (SRI-S2K)Percent of patients with reduction in SELENA-SLEDAI-S2K >=442%50%Odds Ratio (95% CI)1.5 (1.0, 2.2)Percent of patients with no worsening by BILAG index62%68%Odds Ratio (95% CI)1.2 (0.8, 1.9)Percent of patients with no worsening by PGA64%70%Odds Ratio (95% CI)1.3 (0.8, 1.9)Effect on Concomitant Steroid Treatment: In Trial and Trial 3, 46% and 69% of patients, respectively, were receiving prednisone at doses >7.5 mg/day at baseline. The proportion of patients able to reduce their average prednisone dose by at least 25% to <=7.5 mg/day during Weeks 40 through 52 was not consistently significantly different for BENLYSTA plus standard therapy relative to placebo plus standard therapy in both trials. In Trial 2, 17% of patients receiving BENLYSTA 10 mg/kg plus standard therapy and 19% of patients receiving BENLYSTA mg/kg plus standard therapy achieved this level of steroid reduction compared with 13% of patients receiving placebo plus standard therapy. In Trial 3, 19%, 21%, and 12% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA mg/kg, and placebo, respectively, plus standard therapy achieved this level of steroid reduction.Effect on Severe SLE Flares: The probability of experiencing severe SLE flare, as defined by modification of the SELENA Trial flare criteria, which excluded severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated for both Trials and 3. The proportion of patients having at least severe flare over 52 weeks was not consistently significantly different for BENLYSTA plus standard therapy relative to placebo plus standard therapy in both trials. In Trial 2, 18% of patients receiving BENLYSTA 10 mg/kg plus standard therapy and 16% of patients receiving BENLYSTA mg/kg plus standard therapy had severe flare compared with 24% of patients receiving placebo plus standard therapy. In Trial 3, 14%, 18%, and 23% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA mg/kg and placebo, respectively, plus standard therapy had severe flare.. o>=4-point reduction in the SELENA-SLEDAI score, and. ono new British Isles Lupus Assessment Group (BILAG) organ domain score or new BILAG organ domain scores, and. ono worsening (<0.30-point increase) in Physicians Global Assessment (PGA) score.. 14.2Clinical Trials with Intravenous Administration in Adults with Lupus Nephritis Trial 5: Lupus Nephritis BENLYSTA 10 mg/kg IntravenousThe safety and effectiveness of BENLYSTA 10 mg/kg administered intravenously over hour on Days 0, 14, 28, and then every 28 days plus standard therapy were evaluated in 104-week, randomized, double-blind, placebo-controlled trial in 448 patients with active proliferative and/or membranous lupus nephritis (Trial 5). The patients had clinical diagnosis of SLE according to American College of Rheumatology classification criteria; biopsy-proven lupus nephritis Class III, IV, and/or V; and had active renal disease at screening requiring standard therapy: corticosteroids with 1) mycophenolate for induction followed by mycophenolate for maintenance, or 2) cyclophosphamide for induction followed by azathioprine for maintenance. This trial was conducted in Asia, North America, South America, and Europe. The mean age of patients was 33 years (range: 18 to 77); the majority (88%) were female.The primary efficacy endpoint was Primary Efficacy Renal Response (PERR) at Week 104, defined as response at Week 100 confirmed by repeat measurement at Week 104 of the following parameters: urine protein:creatinine ratio (uPCR) <=0.7 g/g and estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m2 or no decrease in eGFR of >20% from pre-flare value.The major secondary endpoints included:oComplete Renal Response (CRR) defined as response at Week 100 confirmed by repeat measurement at Week 104 of the following parameters: uPCR <0.5 g/g and eGFR >=90 mL/min/1.73 m2 or no decrease in eGFR of >10% from pre-flare value.oPERR at Week 52.oTime to renal-related event or death (renal-related event defined as first event of end-stage renal disease, doubling of serum creatinine, renal worsening [defined by quantified increase in proteinuria and/or impaired renal function], or receipt of renal disease-related prohibited therapy due to inadequate lupus nephritis control or renal flare management).The proportion of patients achieving PERR at Week 104 was significantly higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy (Table 6). The major secondary endpoints also showed significant improvement with BENLYSTA plus standard therapy compared with placebo plus standard therapy (Table and Table 7). Table 6. Efficacy Results in Adults with Lupus Nephritis (Trial 5)Efficacy Endpointa Placebo +Standard Therapyn 223BENLYSTA +Standard Therapyn 223Odds Ratio (OR) vs. Placebo(95% CI)eGFR Estimated glomerular filtration rate. PERR at Week 104 was the primary efficacy analysis; CRR at Week 104 and PERR at Week 52 were included in pre-specified testing hierarchy. In order to be considered responder, steroid treatment had to be reduced to <=10 mg/day from Week 24. Patients who discontinued treatment early, received prohibited medication or increases in background standard therapy, or withdrew from the study were considered non-responders. Prohibited medications and increases in background standard therapy were defined as: 1) use of corticosteroids above that allowed by protocol; 2) additional immunosuppressive agents (except topicals) beyond their induction/maintenance regimens; 3) angiotensin converting enzyme inhibitors (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or antimalarials initiated after Week 24; 4) exceeding protocol-permitted doses for standard therapy (cyclophosphamide, azathioprine, mycophenolate); or 5) other biologics, IV immunoglobulin, or plasmapheresis. The percentage of patients who did not take prohibited medications or have an increase in background standard therapy at Week 104 was 83% for BENLYSTA and 74% for placebo. Primary Efficacy Renal Response (PERR) at Week 104b,c Responders32%43%1.6(1.0, 2.3)P 0.031Components of PERR Urine protein:creatinine ratio <=0.7 g/g34%44%1.5(1.0, 2.3) eGFR >=60 mL/min/1.73 m2 or no decrease in eGFR from pre-flare value of >20%50%57%1.3(0.9, 1.9)Complete Renal Response (CRR) at Week 104b,c Responders20%30%1.7(1.1, 2.7)P 0.017Components of CRR Urine protein:creatinine ratio <0.5 g/g29%39%1.6(1.1, 2.4) eGFR >=90 mL/min/1.73 m2 or no decrease in eGFR from pre-flare value of >10%40%47%1.3(0.9, 2.0)PERR at Week 52b Responders35%47%1.6(1.1, 2.4)P 0.025In descriptive subgroup analyses, the PERR and CRR rates were examined by induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III V or Class IV V, or Class V), and uPCR levels at baseline (<3 g/g or >=3 g/g; post-hoc analysis) (Figure 1).Figure 1. Odds Ratio of PERR and CRR at Week 104 across Subgroupsa, (Trial 5)a Class III Focal proliferative lupus nephritis; Class IV Diffuse proliferative lupus nephritis; Class = Membranous lupus nephritis; Class III V Mixed membranous-focal proliferative lupus nephritis; Class IV V Mixed membranous-diffuse proliferative lupus nephritis.b Baseline urine protein:creatinine ratio (uPCR) was post-hoc analysis.The proportion of responders for PERR by visit through Week 104 is shown in Figure 2.Figure 2. Primary Efficacy Renal Response (PERR) in Adults with Lupus Nephritis (+/- Standard Error) by Visita (Trial 5)a Analysis is descriptive; bars represent standard error. The same patients may not have responded at each timepoint.In Trial 5, subjects who received BENLYSTA were significantly less likely to experience renal-related event or death compared with placebo (Table 7). Table 7. Time to Renal-Related Event or Death in Adults with Lupus Nephritis (Trial 5)Efficacy EndpointPlacebo +Standard Therapyn 223BENLYSTA +Standard Therapyn 223Hazard Ratio (HR) vs. Placebo(95% CI)a Time to renal-related event or death included in pre-specified testing hierarchy. When excluding deaths from analysis (1 for BENLYSTA; for placebo), the percentage of patients with renal-related event was 15% for BENLYSTA compared with 27% for placebo (HR 0.5; 95% CI: 0.3, 0.8). Subjects who discontinued treatment, were withdrawn from the study, lost to follow-up, or had treatment failure not related to renal disease were censored on the date of the event. Subjects who completed the 104-week treatment period were censored at the Week 104 visit. Time to event was defined as (event date minus treatment start date plus day). Patients could have had more than one event; the first event contributed to the overall endpoint. Renal worsening was prospectively defined as the development of increased proteinuria and/or impaired renal function defined as: 1) Increased proteinuria (using spot urine): reproducible increase in 24-hour urine protein levels to >1 g/g if the baseline value was <0.2 g/g or >2 g/g if the baseline value was between 0.2 g/g and g/g or more than twice the value at baseline if the baseline value was >1 g/g; and 2) Impaired renal function: reproducible decrease in eGFR of >20% accompanied by at least of the following: proteinuria (>1 g/g), red blood cell casts, or white blood cell casts. Renal-related treatment failure was prospectively defined as intake of prohibited medications for adjudicated inadequate lupus nephritis control or renal flare management. Time to Renal-Related Event or Deatha Percentage of patients with eventb Number of patients with event28%6316%35Time to eventc 0.5(0.3, 0.8)P 0.001Components of endpointd Percentage of patients with event End-stage renal disease (ESRD)0.4%1% Doubling of serum creatinine from baseline4%1% Renal worseninge 18%8% Renal-related treatment failuref 16%9% Death1%0.4%In descriptive subgroup analyses of time to renal-related event or death, results were consistent with the overall endpoint regardless of induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III V or Class IV V, or Class V; post-hoc analysis), and baseline proteinuria (<3 g/g or >=3 g/g; post-hoc analysis). The treatment difference was primarily driven by the renal worsening and renal-related treatment failure components of the endpoint.. oComplete Renal Response (CRR) defined as response at Week 100 confirmed by repeat measurement at Week 104 of the following parameters: uPCR <0.5 g/g and eGFR >=90 mL/min/1.73 m2 or no decrease in eGFR of >10% from pre-flare value.. oPERR at Week 52.. oTime to renal-related event or death (renal-related event defined as first event of end-stage renal disease, doubling of serum creatinine, renal worsening [defined by quantified increase in proteinuria and/or impaired renal function], or receipt of renal disease-related prohibited therapy due to inadequate lupus nephritis control or renal flare management).. Figure 1. Figure 2. 14.3Clinical Trials with Intravenous Administration in Pediatric Patients with SLE Trial 6: SLE BENLYSTA 10 mg/kg in Pediatric Patients IntravenousThe safety and efficacy of BENLYSTA was evaluated in an international, randomized, double-blind, placebo-controlled, 52-week, pharmacokinetics (PK), efficacy and safety study conducted in 93 pediatric patients with clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Patients had active SLE disease, defined as SELENA-SLEDAI score >=6 and positive autoantibodies at screening as defined in the adult trials. Patients were on stable SLE treatment regimen (standard of care) and had similar inclusion and exclusion criteria as in the adult studies. The median age was 15 years (range: to 17). The majority (95%) of patients were female. More than 50% of patients had or more active organ systems involved at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (91%), immunologic (74%), and musculoskeletal (73%). Overall, 19% of pediatric patients had some degree of renal activity and less than 7% had activity in the cardio-respiratory, hematologic, CNS or vascular systems. Randomization into age-related treatment cohorts was stratified by screening SELENA-SLEDAI scores (6 to 12 vs >13) and age (5 to 11 years vs 12 to 17 years).The primary efficacy endpoint was the SLE Responder Index (SRI-4) at Week 52, as described in the adult intravenous trials. There was numerically higher proportion of pediatric patients achieving response in SRI-4 and its components in pediatric patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy (Table 8).Table 8. Pediatric Response Rate at Week 52a (Trial 6)a Based on non-powered trial.ResponsePlacebo +Standard Therapy(n 40)BENLYSTA10 mg/kg +Standard Therapy(n 53)SLE Responder Index44%53%Odds Ratio(95% CI) vs. Placebo1.49(0.64, 3.46)Components of SLE Responder Index Percent of patients with reduction in SELENA-SLEDAI >=444%55% Percent of patients with no worsening by BILAG index62%74% Percent of patients with no worsening by PGA67%76%Other endpoints SRI-6 using SELENA SLEDAI >=6-point reduction34%41% Proportion of patients with sustained SRI response41%43%Effect on Concomitant Steroid Treatment: At baseline, 95% of pediatric patients were receiving prednisone. Among those pediatric patients, 20% of pediatric patients receiving BENLYSTA plus standard therapy reduced their average prednisone dose by at least 25% per day during Weeks 44 through 52 compared with 21% of pediatric patients on placebo plus standard therapy.Effect on Severe SLE Flares: In Trial 6, the probability of experiencing severe SLE flare, as measured by the modified SELENA-SLEDAI Flare Index, excluding severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated. The proportion of pediatric patients reporting at least one severe flare during the study was numerically lower in pediatric patients receiving BENLYSTA plus standard therapy (17%) compared with those receiving placebo plus standard therapy (35%). Pediatric patients receiving BENLYSTA 10 mg/kg plus standard therapy had 64% lower risk of experiencing severe flare during the 52 weeks of observation, relative to the placebo plus standard therapy group. Of the pediatric patients experiencing severe flare, the median time to the first severe flare was 150 days in pediatric patients receiving BENLYSTA plus standard therapy compared with 113 days in pediatric patients receiving placebo plus standard therapy.. 14.4 Clinical Trials with Subcutaneous Administration in Adults with SLE. Trial 7: SLE BENLYSTA 200 mg SubcutaneousThe safety and effectiveness of BENLYSTA administered subcutaneously were evaluated in randomized, double-blind, placebo-controlled trial involving 836 adult patients with SLE according to the American College of Rheumatology criteria (Trial 7, NCT 01484496). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. The trial (2:1 randomization) evaluated BENLYSTA 200 mg once weekly plus standard therapy (n 556) compared with placebo once weekly plus standard therapy (n 280) over 52 weeks in patients with active SLE disease. Patients had to have SELENA-SLEDAI score of >=8 and positive autoantibody test (anti-nuclear antibody [ANA] and/or anti-double-stranded DNA [anti-dsDNA]) results at screening.No significant differences in baseline patient characteristics were observed between treatment groups. In some countries, treatment with B-cell-targeted agent was permitted if received year or more prior to baseline; otherwise, treatment with B-cell-targeted agent was not permitted. Patients were excluded from the trial if they were currently receiving other biologic agents. Anti-tumor necrosis factor therapy, intravenous cyclophosphamide, interleukin-1 receptor antagonist, intravenous immunoglobulin (IVIG), prednisone >100 mg/day, and plasmapheresis were not permitted within the previous months or during the trial. The trial was conducted in North America, South America, Europe, and Asia. Baseline concomitant medications included corticosteroids (86%), antimalarials (69%), and immunosuppressives (46%, including azathioprine, methotrexate, and mycophenolate). Most patients (approximately 80%) were receiving or more classes of SLE medications.More than 50% of patients had or more active organ systems involved at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (88%), musculoskeletal (78%), and immunologic (76%). Overall, 12% of patients had some degree of renal activity and less than 15% of patients had activity in the vascular, cardio-respiratory, or CNS systems. Patients were stratified by disease severity based on their SELENA-SLEDAI score (<=9 vs. >=10), complement level (C3 and/or C4 low vs. other), and race (Black vs. other), and then randomly assigned to receive BENLYSTA 200 mg plus standard therapy or placebo once weekly plus standard therapy.The primary efficacy endpoint was the SLE Responder Index-4 (SRI-4) at Week 52 as described in the intravenous trials. Secondary efficacy endpoints included time to first severe flare (as measured by the modified SELENA-SLEDAI SLE Flare Index) and the proportion of patients receiving prednisone >7.5 mg/day at baseline whose average prednisone dose had been reduced by >=25% to <=7.5 mg/day during Weeks 40 through 52.The proportion of patients achieving an SRI-4 response was significantly higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. The trends comparing the treatment groups with respect to the probability of response for the individual components of the endpoint were consistent with that of the SRI-4 (Table 9).Table 9. Clinical Response Rate in Patients with SLE after 52 Weeks of Treatment (Trial 7)a Patients dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. higher proportion of patients receiving placebo plus standard therapy were considered as failures for this reason compared with the group receiving BENLYSTA plus standard therapy.ResponsePlacebo +Standard Therapy(n 279)BENLYSTA +Standard Therapy(n 554)SLE Responder Index-4 (SRI-4)a 48%61%P 0.0006Odds Ratio(95% CI) vs. placebo1.7(1.3, 2.3)Components of SLE Responder Index-4 (SRI-4)Percent of patients with reduction in SELENA-SLEDAI >=449%62%Percent of patients with no worsening by BILAG index74%81%Percent of patients with no worsening by PGA73%81%The reduction in disease activity seen in the SRI-4 was related primarily to improvement in the most commonly involved organ systems, namely, mucocutaneous, musculoskeletal, immunologic, and vascular.The proportion of SRI-4 responders by visit through Week 52 is shown in Figure 3.Figure 3. Proportion (%) of SRI-4 Responders (+/- Standard Error) by Visita The same patients may not have responded at each timepoint.Effect in Black/African-American Patients: Exploratory sub-group analyses of SRI-4 response rate in Black patients (n 91) were performed. The SRI-4 response rate in Black patients receiving BENLYSTA plus standard therapy was 45% (26/58) compared with 39% (13/33) in the group receiving placebo plus standard therapy [see Use in Specific Populations (8.8)].Effect on Concomitant Steroid Treatment: At baseline, 60% of patients were receiving prednisone at doses >7.5 mg/day. Among these patients, 18% of patients receiving BENLYSTA plus standard therapy reduced their average prednisone dose by at least 25% to <=7.5 mg/day during Weeks 40 through 52 compared with 12% of patients on placebo plus standard therapy; this difference was not statistically significant (OR 1.65 [95% CI: 0.95, 2.84]).Effect on Severe SLE Flares: The probability of experiencing severe SLE flare, as measured by the modified SELENA-SLEDAI SLE Flare Index, excluding severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated. The proportion of patients reporting at least severe flare during the study was lower in patients treated with BENLYSTA plus standard therapy (11%) compared with those receiving placebo plus standard therapy (18%). Patients treated with BENLYSTA plus standard therapy had 49% lower risk of experiencing at least severe flare during the 52 weeks of observation, relative to the patients receiving placebo plus standard therapy (HR 0.51 [95% CI: 0.35, 0.74]). Of the patients experiencing severe flare, the median time to the first severe flare was delayed in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy (171 days vs. 118 days).. Figure 3. Proportion (%) of SRI-4 Responders (+/- Standard Error) by Visita.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. BENLYSTA may be administered as an intravenous infusion in patients aged years and older or as subcutaneous injection in patients aged 18 years and older. Vials are intended for intravenous use only (not for subcutaneous use) and autoinjectors and prefilled syringes are intended for subcutaneous use only (not for intravenous use).. oIntravenous Administration in Adults with SLE or Lupus Nephritis and Pediatric Patients with SLE-10 mg/kg at 2-week intervals for the first doses and at 4-week intervals thereafter. Reconstitute, dilute, and administer as an intravenous infusion over period of hour. (2.1)-Consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions. (2.1)oSubcutaneous Administration in Adults with SLE-200 mg once weekly. (2.2)oSubcutaneous Administration in Adults with Lupus Nephritis-See Section 2.2.. oIntravenous Administration in Adults with SLE or Lupus Nephritis and Pediatric Patients with SLE-10 mg/kg at 2-week intervals for the first doses and at 4-week intervals thereafter. Reconstitute, dilute, and administer as an intravenous infusion over period of hour. (2.1)-Consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions. (2.1). oSubcutaneous Administration in Adults with SLE-200 mg once weekly. (2.2). oSubcutaneous Administration in Adults with Lupus Nephritis-See Section 2.2.. 2.1 Intravenous Preparation and Dosing Instructions. Recommended Intravenous Dosage Regimen -- Adults with SLE or Lupus Nephritis and Pediatric Patients with SLEBENLYSTA for intravenous use must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus.The recommended intravenous dosage regimen is 10 mg/kg at 2-week intervals for the first doses and at 4-week intervals thereafter. Reconstitute, dilute, and administer as an intravenous infusion over period of hour. 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 serious hypersensitivity reaction [see Contraindications (4), Warnings and Precautions (5.2)].Premedication Recommendations prior to Intravenous UsePrior to intravenous dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions [see Warnings and Precautions (5.2, 5.3), Adverse Reactions (6.1)].Preparation of Intravenous SolutionsBENLYSTA for intravenous use is provided as lyophilized powder in single-dose vial and should be reconstituted and diluted by healthcare professional using aseptic technique as follows. Use of 21- to 25-gauge needle is recommended when piercing the vial stopper for reconstitution and dilution.Reconstitution Instructions for Intravenous Use:1.Remove the vial of BENLYSTA from the refrigerator and allow to stand for 10 to 15 minutes for the vial to reach room temperature.2.Reconstitute the BENLYSTA powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain concentration of 80 mg/mL belimumab.oReconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.oReconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP. 3.The stream of sterile water 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 during reconstitution, gently swirling the vial for 60 seconds every minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight.4.If mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.5.Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable.Dilution Instructions for Intravenous Use:1.Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), 0.45% Sodium Chloride Injection, USP (half-normal saline), or Lactated Ringers Injection, USP to volume of 250 mL for intravenous infusion. For patients whose body weight is less than or equal to 40 kg, 100 mL may be used such that the resulting belimumab concentration in the infusion bag does not exceed mg/mL. From 250-mL (or 100-mL) infusion bag or bottle of normal saline, half-normal saline, or Lactated Ringers Injection, withdraw and discard volume equal to the volume of the reconstituted solution of BENLYSTA required for the patients dose. Then add the required volume of the reconstituted solution of BENLYSTA 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.2.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.3.The reconstituted solution of BENLYSTA, if not used immediately, should be stored protected from direct sunlight and refrigerated at 36F to 46F (2C to 8C). Solutions of BENLYSTA diluted in normal saline, half-normal saline, or Lactated Ringers Injection may be stored at 36F to 46F (2C to 8C) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed hours.4.No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed.Administration Instructions for Intravenous Use1.The diluted solution of BENLYSTA should be administered by intravenous infusion over period of hour.2.BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis [see Warnings and Precautions (5.2)].3.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 coadministration of BENLYSTA with other agents.. 1.Remove the vial of BENLYSTA from the refrigerator and allow to stand for 10 to 15 minutes for the vial to reach room temperature.. 2.Reconstitute the BENLYSTA powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain concentration of 80 mg/mL belimumab.oReconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.oReconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP. oReconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.. oReconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.. 3.The stream of sterile water 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 during reconstitution, gently swirling the vial for 60 seconds every minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight.. 4.If mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.. 5.Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable.. 1.Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), 0.45% Sodium Chloride Injection, USP (half-normal saline), or Lactated Ringers Injection, USP to volume of 250 mL for intravenous infusion. For patients whose body weight is less than or equal to 40 kg, 100 mL may be used such that the resulting belimumab concentration in the infusion bag does not exceed mg/mL. From 250-mL (or 100-mL) infusion bag or bottle of normal saline, half-normal saline, or Lactated Ringers Injection, withdraw and discard volume equal to the volume of the reconstituted solution of BENLYSTA required for the patients dose. Then add the required volume of the reconstituted solution of BENLYSTA 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.. 2.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.. 3.The reconstituted solution of BENLYSTA, if not used immediately, should be stored protected from direct sunlight and refrigerated at 36F to 46F (2C to 8C). Solutions of BENLYSTA diluted in normal saline, half-normal saline, or Lactated Ringers Injection may be stored at 36F to 46F (2C to 8C) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed hours.. 4.No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed.. 1.The diluted solution of BENLYSTA should be administered by intravenous infusion over period of hour.. 2.BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis [see Warnings and Precautions (5.2)].. 3.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 coadministration of BENLYSTA with other agents.. 2.2 Subcutaneous Dosing Instructions. Subcutaneous dosing of BENLYSTA has not been evaluated and is not approved for patients younger than 18 years of age.Recommended Subcutaneous Dosage Regimen -- Adult Patients with SLEThe recommended dosage is 200 mg once weekly given as subcutaneous injection in the abdomen or thigh. Subcutaneous dosing is not based on weight.If transitioning from intravenous therapy with BENLYSTA to subcutaneous administration, administer the first subcutaneous dose to weeks after the last intravenous dose.Recommended Subcutaneous Dosage Regimen -- Adult Patients with Lupus NephritisIn patients initiating therapy with BENLYSTA for active lupus nephritis [see Clinical Studies 14.2)], the recommended dosage regimen is 400-mg dose (two 200-mg injections) once weekly for doses, then 200 mg once weekly thereafter. The dose is given via subcutaneous injection in the abdomen or thigh. The 400-mg dose for active lupus nephritis requires administration of autoinjectors or prefilled syringes as described below.A patient with lupus nephritis may transition from intravenous therapy with BENLYSTA to subcutaneous therapy any time after the patient completes the first intravenous doses. If transitioning, administer the first subcutaneous dose of 200 mg to weeks after the last intravenous dose.Administration Instructions for Subcutaneous Injection 1. It is recommended that the first subcutaneous injection of BENLYSTA should be under the supervision of healthcare professional. The healthcare provider should provide proper training in subcutaneous technique and education about signs and symptoms of hypersensitivity reactions [see Warning and Precautions (5.2)]. patient may self-inject or the patient caregiver may administer BENLYSTA subcutaneously after the healthcare provider determines it is appropriate. 2. Instruct the patient or patient caregiver to follow the directions for administration provided in the Instructions for Use. 3. Instruct the patient to remove the autoinjector or prefilled syringe from the refrigerator and allow it to sit at room temperature for 30 minutes prior to the subcutaneous injection. Do not warm BENLYSTA in any other way. 4. Prior to administration, instruct the patient or patient caregiver to visually inspect the window of the autoinjector or the prefilled syringe for particulate matter or discoloration. BENLYSTA should be clear to opalescent and colorless to pale yellow. Do not use BENLYSTA if the product exhibits discoloration or particulate matter. Instruct the patient not to use the BENLYSTA autoinjector or prefilled syringe if dropped on hard surface. 5. When injecting in the same body region, advise the patient to use different injection site for each injection; never give injections into areas where the skin is tender, bruised, red, or hard. When 400-mg dose is administered at the same site, it is recommended that the individual 200-mg injections be administered at least cm (approximately inches) apart. 6. Instruct the patient to administer BENLYSTA 200 mg once week, preferably on the same day each week. 7. If dose is missed, instruct the patient to administer dose as soon as the patient remembers. Thereafter, the patient can resume dosing on their usual day of administration or start new weekly schedule from the day that the missed dose was administered.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseBENLYSTA (ben-LIST-ah)(belimumab)injection, for subcutaneous usePrefilled SyringeRead this Instructions for Use before you start to use BENLYSTA and each time you refill your prescription. There may be new information. You should also receive training from your healthcare provider on how to use the prefilled syringe the right way. If you do not follow these instructions the prefilled syringe may not work properly. BENLYSTA is for use under the skin only (subcutaneous).Important Storage InformationoKeep refrigerated until 30 minutes before use.oKeep in the original package until time of use to protect from light.oDo not freeze BENLYSTA.oKeep away from heat and sunlight.oDo not use and do not place back in the refrigerator if BENLYSTA is left out for more than 12 hours.oKeep out of the reach of children.Important WarningsoThe prefilled syringe should be used only time and then thrown away. See below, Dispose of used prefilled syringe and inspect.oDo not share your BENLYSTA prefilled syringe with other people. You may give other people serious infection or get serious infection from them.oDo not shake the prefilled syringe.oDo not use if dropped onto hard surface.oDo not remove the Needle Cap until right before the injection. BENLYSTA Prefilled Syringe PartsBefore useAfter Use Needle is covered by Needle GuardSupplies needed for the injectionBENLYSTA Prefilled SyringeAlcohol Swab (not included)Gauze Pad or Cotton Ball (not included)Sharps Container (not included)1 Gather and check suppliesGather suppliesoRemove sealed tray containing prefilled syringe from the refrigerator.oFind comfortable, well-lit, and clean surface and place the following supplies within reach:oBENLYSTA Prefilled SyringeoAlcohol Swab (not included)oGauze Pad or Cotton Ball (not included)oSharps Container (not included)oDo not perform the injection if you do not have all the supplies listed.Check expiration dateoPeel back the film of the tray and remove the prefilled syringe by holding the middle of the syringe body.oCheck the expiration date on the prefilled syringe. See Figure A.oDo not use if the expiration date has passed.2 Prepare and inspect the BENLYSTA Prefilled SyringeAllow to come to room temperatureoAllow the prefilled syringe to sit at room temperature for 30 minutes. See Figure B. oDo not warm the prefilled syringe in any other way. For example, do not warm in microwave oven, hot water, or in direct sunlight.oDo not remove the Needle Cap during this step.Inspect BENLYSTA solutionoLook in the Inspection Window to check that the BENLYSTA solution is colorless to slightly yellow in color. See Figure C.oIt is normal to see or more air bubbles in the solution.oDo not use if the solution looks cloudy, discolored, or has particles.3 Choose and clean the injection siteChoose the injection siteoChoose where to inject (abdomen or thigh). See Figure D.oIf you need injections to complete your dose, leave at least inches between each injection if using the same site.oAvoid injecting into the same site each time or in areas where the skin is tender, bruised, red, or hard. oDo not inject within inches of the belly button.Clean the injection siteoWash your hands.oClean the injection site by wiping it with an Alcohol Swab. Allow the skin to air dry. See Figure E.oDo not touch this area again before giving the injection.4 Prepare for the injectionRemove the Needle CapoDo not remove the Needle Cap until right before you give the injection.oHold the prefilled syringe by the body and with the Needle facing away from you. Remove the Needle Cap by pulling it straight off. See Figure F.oYou may see drop of liquid at the end of the Needle. This is normal.oDo not let the Needle touch any surface.oDo not push any air bubbles out of the prefilled syringe.oDo not put the Needle Cap back onto the prefilled syringe.oKeep your hands away from the Plunger to avoid pushing it before injecting.5 Inject BENLYSTAInsert the NeedleoHold the prefilled syringe in one hand and use your free hand to gently pinch the skin around the injection site. See Figure G.oInsert the entire Needle into the pinched area of the skin at slight 45-degree angle using dart-like motion.oAfter the Needle is completely inserted, release the pinched skin.Complete the injectionoPush the Plunger all the way down until all of the solution is injected. See Figure H.oWhile keeping your hold on the syringe, slowly move your thumb back, allowing the Plunger to rise up. The Needle will automatically rise up into the Needle Guard. See Figure I.6 Dispose of used prefilled syringe and inspectDispose of the used prefilled syringeThrow away (dispose of) the used syringe and Needle Cap in Sharps Container. See Figure J.oPut your used syringe and sharps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.oIf you do not have an FDA-cleared sharps disposal container, you may use household container that:ois made of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,ois upright and stable during use,ois leak-resistant, andoproperly labeled to warn of hazardous waste inside the container.oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to: http://www.fda.gov/safesharpsdisposal.oDo not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Inspect the injection siteoThere may be small amount of blood at the injection site. If needed, press Cotton Ball or Gauze Pad on the injection site.oDo not rub the injection site.Additional informationFor more information about BENLYSTA, go to www.BENLYSTA.com or call 1-877-423-6597.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Trademarks are owned by or licensed to the GSK group of companies.Manufactured by GlaxoSmithKline LLC Philadelphia, PA 19112, U.S. License No. 1727, andDistributed by GlaxoSmithKline Research Triangle Park, NC 27709(C)2021 GSK group of companies or its licensor.BNL:4IFU-SRevised March 2021 Instructions for UseBENLYSTA (ben-LIST-ah)(belimumab)injection, for subcutaneous usePrefilled AutoinjectorRead this Instructions for Use before you start to use BENLYSTA and each time you refill your prescription. There may be new information. You should also receive training from your healthcare provider on how to use the autoinjector the right way. If you do not follow these instructions the autoinjector may not work properly. BENLYSTA is for use under the skin only (subcutaneous).Important Storage InformationoKeep refrigerated until 30 minutes before use. oKeep in the original package until time of use to protect from light.oDo not freeze BENLYSTA. oKeep away from heat and sunlight.oDo not use and do not place back in the refrigerator if BENLYSTA is left out for more than 12 hours.oKeep out of the reach of children.Important WarningsoThe autoinjector should be used only time and then thrown away. See below, Dispose of used autoinjector and inspect.oDo not share your BENLYSTA Autoinjector with other people. You may give other people serious infection or get serious infection from them.oDo not shake the autoinjector.oDo not use if dropped onto hard surface.oDo not remove the Ring Cap until right before the injection. BENLYSTA Autoinjector PartsSupplies needed for the injectionBENLYSTA AutoinjectorAlcohol Swab (not included)Gauze Pad or Cotton Ball (not included)Sharps Container (not included)1 Gather and check suppliesGather suppliesoRemove sealed tray containing an autoinjector from the refrigerator.oFind comfortable, well-lit, and clean surface and place the following supplies within reach:oBENLYSTA AutoinjectoroAlcohol Swab (not included)oGauze Pad or Cotton Ball (not included)oSharps Container (not included)oDo not perform the injection if you do not have all the supplies listed.Check expiration dateoPeel back the film of the tray and remove the autoinjector.oCheck the expiration date on the autoinjector. See Figure A.oDo not use if the expiration date has passed.2 Prepare and inspect the BENLYSTA AutoinjectorAllow to come to room temperatureoAllow the autoinjector to sit at room temperature for 30 minutes. See Figure B.oDo not warm the autoinjector in any other way. For example, do not warm in microwave oven, hot water, or in direct sunlight.oDo not remove the Ring Cap during this step.Inspect BENLYSTA solutionoLook in the Inspection Window to check that the BENLYSTA solution is colorless to slightly yellow in color. See Figure C.oIt is normal to see or more air bubbles in the solution.oDo not use if the solution looks cloudy, discolored, or has particles.3 Choose and clean the injection siteChoose the injection siteoChoose where to inject (abdomen or thigh). See Figure D.oIf you need injections to complete your dose, leave at least inches between each injection if using the same site.oAvoid injecting into the same site each time or in areas where the skin is tender, bruised, red, or hard.oDo not inject within inches of the belly button.Clean the injection siteoWash your hands.oClean the injection site by wiping it with an Alcohol Swab. Allow the skin to air dry. See Figure E. oDo not touch this area again before giving the injection.4 Prepare for the injectionRemove the Ring CapoDo not remove the Ring Cap until right before you give the injection.oRemove the Ring Cap by pulling or twisting it off. The Ring Cap may be twisted off in either clockwise or counter-clockwise direction. See Figure F.oDo not put the Ring Cap back onto the autoinjector.Position the autoinjectoroHold the autoinjector comfortably so that you can see the Inspection Window. It is important that you can look at the Inspection Window while giving the injection. You will look at the Inspection Window to:osee that the purple indicator is moving while you are injecting.osee that the purple indicator has stopped to make sure that the dose is complete. See Figure G.oPosition the autoinjector straight over the injection site at 90-degree angle. Make sure the Gold Needle Guard is flat on the skin.5 Inject BENLYSTAStart the injectionoFirmly press the autoinjector all the way down onto the injection site and hold in place. See Figure H.oThis will insert the needle and start the injection.oYou may hear first click at the start of the injection and see the Purple Indicator start to move through the Inspection Window. See Figure I.Complete the injectionoContinue to hold the autoinjector down until you see that the Purple Indicator has stopped moving. You may hear second click few seconds before the Purple Indicator stops moving. See Figure J.oThe injection may take up to 15 seconds to complete.oWhen the injection is complete, lift the autoinjector from the injection site.6 Dispose of used autoinjector and inspectDispose of the used autoinjectorThrow away (dispose of) the used autoinjector and Ring Cap in Sharps Container. See Figure K.oPut your used autoinjector in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) in your household trash.oIf you do not have an FDA-cleared sharps disposal container, you may use household container that:ois made of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,ois upright and stable during use,ois leak-resistant, andoproperly labeled to warn of hazardous waste inside the container.oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to: http://www.fda.gov/safesharpsdisposal.oDo not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Inspect the injection siteoThere may be small amount of blood at the injection site. If needed, press Cotton Ball or Gauze Pad on the injection site.oDo not rub the injection site.Additional informationFor more information about BENLYSTA, go to www.BENLYSTA.com or call 1-877-423-6597.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Trademarks are owned by or licensed to the GSK group of companies.Manufactured by GlaxoSmithKline LLC Philadelphia, PA 19112, U.S. License No. 1727, andDistributed by GlaxoSmithKline Research Triangle Park, NC 27709(C)2021 GSK group of companies or its licensor.BNL:4IFU-ARevised March 2021. oKeep refrigerated until 30 minutes before use.. oKeep in the original package until time of use to protect from light.. oDo not freeze BENLYSTA.. oKeep away from heat and sunlight.. oDo not use and do not place back in the refrigerator if BENLYSTA is left out for more than 12 hours.. oKeep out of the reach of children.. oThe prefilled syringe should be used only time and then thrown away. See below, Dispose of used prefilled syringe and inspect.oDo not share your BENLYSTA prefilled syringe with other people. You may give other people serious infection or get serious infection from them.oDo not shake the prefilled syringe.oDo not use if dropped onto hard surface.oDo not remove the Needle Cap until right before the injection. oDo not share your BENLYSTA prefilled syringe with other people. You may give other people serious infection or get serious infection from them.. oDo not shake the prefilled syringe.. oDo not use if dropped onto hard surface.. oDo not remove the Needle Cap until right before the injection.. oRemove sealed tray containing prefilled syringe from the refrigerator.. oFind comfortable, well-lit, and clean surface and place the following supplies within reach:oBENLYSTA Prefilled SyringeoAlcohol Swab (not included)oGauze Pad or Cotton Ball (not included)oSharps Container (not included). oBENLYSTA Prefilled Syringe. oAlcohol Swab (not included). oGauze Pad or Cotton Ball (not included). oSharps Container (not included). oDo not perform the injection if you do not have all the supplies listed.. oPeel back the film of the tray and remove the prefilled syringe by holding the middle of the syringe body.. oCheck the expiration date on the prefilled syringe. See Figure A.. oDo not use if the expiration date has passed.. oAllow the prefilled syringe to sit at room temperature for 30 minutes. See Figure B.. oDo not warm the prefilled syringe in any other way. For example, do not warm in microwave oven, hot water, or in direct sunlight.oDo not remove the Needle Cap during this step.. oDo not warm the prefilled syringe in any other way. For example, do not warm in microwave oven, hot water, or in direct sunlight.. oDo not remove the Needle Cap during this step.. oLook in the Inspection Window to check that the BENLYSTA solution is colorless to slightly yellow in color. See Figure C.. oIt is normal to see or more air bubbles in the solution.oDo not use if the solution looks cloudy, discolored, or has particles.. oDo not use if the solution looks cloudy, discolored, or has particles.. oChoose where to inject (abdomen or thigh). See Figure D.. oIf you need injections to complete your dose, leave at least inches between each injection if using the same site.. oAvoid injecting into the same site each time or in areas where the skin is tender, bruised, red, or hard.. oDo not inject within inches of the belly button.. oDo not inject within inches of the belly button.. oWash your hands.. oClean the injection site by wiping it with an Alcohol Swab. Allow the skin to air dry. See Figure E.. oDo not touch this area again before giving the injection.. oDo not remove the Needle Cap until right before you give the injection.. oHold the prefilled syringe by the body and with the Needle facing away from you. Remove the Needle Cap by pulling it straight off. See Figure F.. oYou may see drop of liquid at the end of the Needle. This is normal.. oDo not let the Needle touch any surface.. oDo not push any air bubbles out of the prefilled syringe.. oDo not put the Needle Cap back onto the prefilled syringe.. oKeep your hands away from the Plunger to avoid pushing it before injecting.. oHold the prefilled syringe in one hand and use your free hand to gently pinch the skin around the injection site. See Figure G.. oInsert the entire Needle into the pinched area of the skin at slight 45-degree angle using dart-like motion.. oAfter the Needle is completely inserted, release the pinched skin.. oPush the Plunger all the way down until all of the solution is injected. See Figure H.. oWhile keeping your hold on the syringe, slowly move your thumb back, allowing the Plunger to rise up. The Needle will automatically rise up into the Needle Guard. See Figure I.. oPut your used syringe and sharps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.. oIf you do not have an FDA-cleared sharps disposal container, you may use household container that:ois made of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,ois upright and stable during use,ois leak-resistant, andoproperly labeled to warn of hazardous waste inside the container.. ois made of heavy-duty plastic,. ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. ois upright and stable during use,. ois leak-resistant, and. oproperly labeled to warn of hazardous waste inside the container.. oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to: http://www.fda.gov/safesharpsdisposal.. oDo not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. oThere may be small amount of blood at the injection site. If needed, press Cotton Ball or Gauze Pad on the injection site.. oDo not rub the injection site.. oKeep refrigerated until 30 minutes before use. oKeep in the original package until time of use to protect from light.. oDo not freeze BENLYSTA. oKeep away from heat and sunlight.. oDo not use and do not place back in the refrigerator if BENLYSTA is left out for more than 12 hours.. oKeep out of the reach of children.. oThe autoinjector should be used only time and then thrown away. See below, Dispose of used autoinjector and inspect.oDo not share your BENLYSTA Autoinjector with other people. You may give other people serious infection or get serious infection from them.oDo not shake the autoinjector.oDo not use if dropped onto hard surface.oDo not remove the Ring Cap until right before the injection. oDo not share your BENLYSTA Autoinjector with other people. You may give other people serious infection or get serious infection from them.. oDo not shake the autoinjector.. oDo not use if dropped onto hard surface.. oDo not remove the Ring Cap until right before the injection.. oRemove sealed tray containing an autoinjector from the refrigerator.. oFind comfortable, well-lit, and clean surface and place the following supplies within reach:oBENLYSTA AutoinjectoroAlcohol Swab (not included)oGauze Pad or Cotton Ball (not included)oSharps Container (not included). oBENLYSTA Autoinjector. oAlcohol Swab (not included). oGauze Pad or Cotton Ball (not included). oSharps Container (not included). oDo not perform the injection if you do not have all the supplies listed.. oPeel back the film of the tray and remove the autoinjector.. oCheck the expiration date on the autoinjector. See Figure A.. oDo not use if the expiration date has passed.. oAllow the autoinjector to sit at room temperature for 30 minutes. See Figure B.. oDo not warm the autoinjector in any other way. For example, do not warm in microwave oven, hot water, or in direct sunlight.. oDo not remove the Ring Cap during this step.. oLook in the Inspection Window to check that the BENLYSTA solution is colorless to slightly yellow in color. See Figure C.. oIt is normal to see or more air bubbles in the solution.. oDo not use if the solution looks cloudy, discolored, or has particles.. oChoose where to inject (abdomen or thigh). See Figure D.. oIf you need injections to complete your dose, leave at least inches between each injection if using the same site.. oAvoid injecting into the same site each time or in areas where the skin is tender, bruised, red, or hard.. oDo not inject within inches of the belly button.. oWash your hands.. oClean the injection site by wiping it with an Alcohol Swab. Allow the skin to air dry. See Figure E.. oDo not touch this area again before giving the injection.. oDo not touch this area again before giving the injection.. oDo not remove the Ring Cap until right before you give the injection.. oRemove the Ring Cap by pulling or twisting it off. The Ring Cap may be twisted off in either clockwise or counter-clockwise direction. See Figure F.. oDo not put the Ring Cap back onto the autoinjector.. oHold the autoinjector comfortably so that you can see the Inspection Window. It is important that you can look at the Inspection Window while giving the injection. You will look at the Inspection Window to:osee that the purple indicator is moving while you are injecting.osee that the purple indicator has stopped to make sure that the dose is complete. See Figure G.. osee that the purple indicator is moving while you are injecting.. osee that the purple indicator has stopped to make sure that the dose is complete. See Figure G.. oPosition the autoinjector straight over the injection site at 90-degree angle. Make sure the Gold Needle Guard is flat on the skin.. oFirmly press the autoinjector all the way down onto the injection site and hold in place. See Figure H.. oThis will insert the needle and start the injection.. oYou may hear first click at the start of the injection and see the Purple Indicator start to move through the Inspection Window. See Figure I.. oContinue to hold the autoinjector down until you see that the Purple Indicator has stopped moving.. You may hear second click few seconds before the Purple Indicator stops moving. See Figure J.. oThe injection may take up to 15 seconds to complete.. oWhen the injection is complete, lift the autoinjector from the injection site.. oPut your used autoinjector in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) in your household trash.. oIf you do not have an FDA-cleared sharps disposal container, you may use household container that:. ois made of heavy-duty plastic,. ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. ois upright and stable during use,. ois leak-resistant, and. oproperly labeled to warn of hazardous waste inside the container.. oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to: http://www.fda.gov/safesharpsdisposal.. oDo not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. oThere may be small amount of blood at the injection site. If needed, press Cotton Ball or Gauze Pad on the injection site.. oDo not rub the injection site.. BENLYSTA prefilled syringe parts. Needle Guard. BENLYSTA prefilled syringe. Gauze Pad or Cotton Ball SuppliesSharpsContainerPFS. FigureAPFS. FigureBPFS. FigureCPFS. FigureDPFS. FigureEPFS. FigureFPFS. FigureGPFS. FigureHPFS. FigureIPFS. FigureJPFS. Autoinjectorpartsopen-viewAI. BENLYSTA autoinjector. Gauze Pad or Cotton Ball. SuppliesSharpsContainerAI. FigureAAI. FigureBAI. FigureCAI. FigureDAI. FigureEAI. FigureFAI. FigureGAI. FigureHAI. FigureIAI. FigureJAI. FigureKAI.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Intravenous Infusion in AdultsSystemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table are based on population parameter estimates from 563 adult patients who received BENLYSTA 10 mg/kg. Table 2. Population Pharmacokinetic Parameters in Adult Patients with SLE after Intravenous Infusion of BENLYSTA 10 mg/kga Intravenous infusions were administered at 2-week intervals for the first doses and at 4-week intervals thereafter.Pharmacokinetic ParameterPopulation Estimates(n 563)Peak concentration (Cmax, mcg/mL)313Area under the curve (AUC0-, daymcg/mL)3,083Distribution half-life (t 1/2 days)1.8Terminal half-life (t 1/2 days)19.4Systemic clearance (CL, mL/day)215Volume of distribution (Vss, L)5Lupus Nephritis: population pharmacokinetic analysis was conducted in 224 adult patients with lupus nephritis who received belimumab 10 mg/kg intravenously (Days 0, 14, 28, and then every 28 days up to 104 weeks) plus standard therapy [see Clinical Studies (14.2)]. In patients with lupus nephritis, due to additional clearance associated with proteinuria, belimumab exposure was initially lower than observed in SLE studies and lower belimumab exposure was observed in patients with higher proteinuria. When the proteinuria was decreased to approximately <=1 g/g after treatment, belimumab clearance and exposure were similar to that observed in patients with SLE who received belimumab 10 mg/kg intravenously. The available data do not support dose adjustment in patients with high proteinuria.Subcutaneous Injection in AdultsSystemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table are based on population parameter estimates from 661 subjects after subcutaneous administration of belimumab 200 mg once weekly. The time to reach maximum serum concentration (Cmax) was 2.6 days (Tmax) after administration at steady state. The bioavailability of belimumab was approximately 74%. With weekly subcutaneous administration there were minor fluctuations around the average concentration (Cavg 104 mcg/mL), with Cmin (97 mcg/mL) being only slightly below Cavg.Table 3. Population Pharmacokinetic Parameters in Adults after Subcutaneous Administration of BENLYSTAPharmacokinetic ParameterPopulation Estimates(n 661)Peak concentration (Cmax, mcg/mL)108Area under the curve (AUC0-, daymcg/mL)726Distribution half-life (t 1/2 days)1.1Terminal half-life (t 1/2 days)18.3Systemic clearance (CL, mL/day)204Volume of distribution (Vss, L)5Lupus Nephritis: Based on population pharmacokinetic modeling and simulation of the subcutaneous 400-mg weekly loading dose, the average belimumab concentration during the first 12 weeks was predicted to be 78 mcg/mL, which is similar to the estimated concentration of 89 mcg/mL for intravenous administration. The loading dose of 400 mg weekly provides steady-state concentrations from Week of dosing. The steady-state average concentrations of subcutaneous administration of belimumab 200 mg once weekly in adults with lupus nephritis are predicted to be similar to those observed in adults with lupus nephritis receiving belimumab 10 mg/kg intravenously every weeks.Specific PopulationsThe following information is based on the population pharmacokinetic analyses of intravenous administration and subcutaneous administration of BENLYSTA.Age: Age did not significantly influence the pharmacokinetics of belimumab, where the majority of subjects were between 18 and 45 years (70% with intravenous dosing; 74% with subcutaneous dosing). Geriatric Patients: Limited pharmacokinetic data are available for elderly patients as less than 2% of the subjects included in the pharmacokinetic analysis were 65 years or older [see Use in Specific Populations (8.5)]. Pediatric Patients: The pharmacokinetic parameters are based on individual parameter estimates from population pharmacokinetic analysis of 53 pediatric patients (Trial 6). Following IV administration of 10 mg/kg on Days 0, 14, and 28, and at 4-week intervals thereafter, belimumab exposures were similar between pediatric and adult subjects with SLE. Steady-state geometric mean Cmax, Cmin, Cavg, and AUC values were 305, 42, 92 mcg/mL, and 2,569 daymcg/mL in the 5- to 11-year-old group, and 317, 52, 112 mcg/mL and 3,126 daymcg/mL in the 12- to 17-year-old group. [See Use in Specific Populations (8.4).] Male and Female Patients: Gender did not significantly influence belimumab pharmacokinetics in the largely female trial population (94% with intravenous dosing; 85% with subcutaneous dosing).Racial Groups: Race did not significantly influence belimumab pharmacokinetics. The racial distribution with intravenous administration was 53% White, 16% Asian, 16% Alaska native/American Indian, and 14% Black in Trials 1, 2, and 3. Trial enrolled only Black patients. The racial distribution with subcutaneous administration (Trial 7) was 61% White, 20% Asian, 11% Black, and 6% Alaska native/American Indian.Weight: Body weight and body mass index (BMI) had no clinically relevant effect on the pharmacokinetics of belimumab administered subcutaneously in adults. No dose adjustment is recommended based on weight or BMI for subcutaneous administration.Patients with Renal Impairment: No formal trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. BENLYSTA was studied in limited number of adult patients with SLE who had mild (CrCl >=60 and <90 mL/min), moderate (CrCl >=30 and <60 mL/min), or severe (CrCl >=15 and <30 mL/min) renal impairment: 770 patients with mild renal impairment, 261 patients with moderate renal impairment, and 14 patients with severe renal impairment received belimumab intravenously; 121 patients with mild renal impairment and 30 patients with moderate renal impairment received belimumab subcutaneously. [See Use in Specific Populations (8.6).] Patients with Hepatic Impairment: No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics. [See Use in Specific Populations (8.7).] Drug Interaction StudiesNo formal drug interaction studies have been conducted with BENLYSTA. Concomitant use of mycophenolate, cyclophosphamide, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and/or HMG-CoA reductase inhibitors did not significantly influence belimumab pharmacokinetics. Coadministration of steroids and angiotensin-converting enzyme (ACE) inhibitors resulted in an increase of systemic clearance of belimumab that was not clinically significant because the magnitude was well within the range of normal variability of clearance. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated.. Geriatric Patients: Limited pharmacokinetic data are available for elderly patients as less than 2% of the subjects included in the pharmacokinetic analysis were 65 years or older [see Use in Specific Populations (8.5)].. Pediatric Patients: The pharmacokinetic parameters are based on individual parameter estimates from population pharmacokinetic analysis of 53 pediatric patients (Trial 6). Following IV administration of 10 mg/kg on Days 0, 14, and 28, and at 4-week intervals thereafter, belimumab exposures were similar between pediatric and adult subjects with SLE. Steady-state geometric mean Cmax, Cmin, Cavg, and AUC values were 305, 42, 92 mcg/mL, and 2,569 daymcg/mL in the 5- to 11-year-old group, and 317, 52, 112 mcg/mL and 3,126 daymcg/mL in the 12- to 17-year-old group. [See Use in Specific Populations (8.4).].

SPL MEDGUIDE SECTION.

MEDICATION GUIDEBENLYSTA (ben-LIST-ah)(belimumab)for injection, for intravenous useBENLYSTA (ben-LIST-ah)(belimumab)injection, for subcutaneous useWhat is the most important information should know about BENLYSTAImmunosuppressive agents, including BENLYSTA can cause serious side effects. Some of these side effects may cause death. The following are serious adverse reactions that have occurred in patients receiving BENLYSTA:1.Infections. Infections could be serious, leading to hospitalization or death. Tell your healthcare provider right away if you have any of the following symptoms of an infection:ofeverochillsopain or burning with urinationourinating oftenocoughing up mucusowarm, red, or painful skin or sores on your body2.Allergic (hypersensitivity) reactions. Serious allergic reactions can happen on the day of, or in the days after, receiving BENLYSTA and may cause death. Your healthcare provider will watch you closely while you are receiving BENLYSTA given intravenously (infusion) and after your infusion for signs of reaction. Allergic reactions can sometimes be delayed. Tell your healthcare provider right away if you have any of the following symptoms of an allergic reaction following use of BENLYSTA:oitchingoswelling of the face, lips, mouth, tongue, or throatotrouble breathingoanxiousnessolow blood pressureodizziness or faintingoheadacheonauseaoskin rash3.Mental health problems and suicide. Symptoms of mental health problems can occur. Tell your healthcare provider right away if you have any of the following symptoms:othoughts of suicide or dyingoattempt to commit suicideotrouble sleeping (insomnia)onew or worse anxietyonew or worse depressionoacting on dangerous impulsesoother unusual changes in your behavior or moodothoughts of hurting yourself or othersWhat is BENLYSTABENLYSTA is prescription medicine used to treat patients with active systemic lupus erythematosus (SLE or lupus) who are receiving other lupus medicines. BENLYSTA is also used to treat adult patients with active lupus nephritis (lupus-related kidney inflammation) who are receiving other lupus medicines.Both intravenous and subcutaneous dosing of BENLYSTA are approved for adults with SLE and lupus nephritis.Intravenous dosing of BENLYSTA is approved in children aged years and older with SLE.BENLYSTA contains belimumab which is in group of medicines called monoclonal antibodies. Lupus is disease of the immune system (the body system that fights infection). When given together with other medicines for lupus, BENLYSTA decreases lupus disease activity more than other lupus medicines alone.oIt is not known if BENLYSTA is safe and effective in people with severe active central nervous system lupus.Do not use BENLYSTA if you:oare allergic to belimumab or any of the ingredients in BENLYSTA. See the end of this Medication Guide for complete list of ingredients in BENLYSTA.Before you receive BENLYSTA, tell your healthcare provider about all of your medical conditions, including if you:othink you have an infection or have infections that keep coming back. You should not receive BENLYSTA if you have an infection unless your healthcare provider tells you to. See What is the most important information should know about BENLYSTAohave or have had mental health problems such as depression or thoughts of suicide.ohave recently received vaccination or if you think you may need vaccination. If you are receiving BENLYSTA, you should not receive live vaccines.oare allergic to other medicines.oare receiving other biologic medicines or monoclonal antibodies.ohave or have had any type of cancer.oare pregnant or plan to become pregnant. It is not known if BENLYSTA will harm your unborn baby. You should talk to your healthcare provider about whether to prevent pregnancy while on BENLYSTA. If you choose to prevent pregnancy, you should use an effective method of birth control while receiving BENLYSTA and for at least months after the final dose of BENLYSTA.oTell your healthcare provider right away if you become pregnant during your treatment with BENLYSTA or if you think you may be pregnant.oIf you become pregnant while receiving BENLYSTA, talk to your healthcare provider about enrolling in the BENLYSTA Pregnancy Registry. You can enroll in this registry by calling 1-877-681-6296. The purpose of this registry is to monitor the health of you and your baby.oare breastfeeding or plan to breastfeed. It is not known if BENLYSTA passes into your breast milk. You and your healthcare provider should talk about whether or not you should receive BENLYSTA and breastfeed.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of your medicines with you to show to your healthcare provider and pharmacist when you get new medicine.How will receive BENLYSTAWhen administered intravenously (by vein)oYou will be given BENLYSTA by healthcare provider through needle placed in vein (IV infusion). It takes about hour to give you the full dose of BENLYSTA.oYour healthcare provider will tell you how often you should receive BENLYSTA.oYour healthcare provider may give you medicines before you receive BENLYSTA to help reduce your chance of having reaction. healthcare provider will watch you closely while you are receiving BENLYSTA and after your infusion for signs of reaction. healthcare provider will review the signs and symptoms of possible allergic reactions that could happen after your infusion.When administered subcutaneously (under your skin)oYour healthcare provider will tell you how often you should use BENLYSTA. Use BENLYSTA exactly as your healthcare provider tells you to.oRead the Instructions for Use that comes with BENLYSTA for instructions about the right way to give your injections at home.oBENLYSTA may be prescribed as single-dose autoinjector or as single-dose prefilled syringe.oBefore you use BENLYSTA, your healthcare provider will show you or your caregiver how to give the injections and review the signs and symptoms of possible allergic reactions.oBENLYSTA is injected under your skin (subcutaneously) of your stomach (abdomen) or thigh.oUse BENLYSTA once week on the same day each week. If you have lupus nephritis, one dose may be injections.oIf you miss your dose of BENLYSTA on your planned day, inject dose as soon as you remember. Then, inject your next dose at your regularly scheduled time or continue weekly dosing based on the new day injected. In case you are not sure when to inject BENLYSTA, call your healthcare provider.What are the possible side effects of BENLYSTABENLYSTA can cause serious side effects, including:See What is the most important information should know about BENLYSTAoProgressive multifocal leukoencephalopathy (PML). PML is serious and life-threatening brain infection. Your chance of getting PML may be higher if you are treated with medicines that weaken your immune system, including BENLYSTA. PML can result in death or severe disability. If you notice any new or worsening medical problems such as those below, tell your healthcare provider right away:omemory lossotrouble thinkingodizziness or loss of balanceodifficulty talking or walkingoloss of visionoCancer. BENLYSTA may reduce the activity of your immune system. Medicines that affect the immune system may increase your risk of certain cancers.The most common side effects of BENLYSTA include:onauseaodiarrheaofeverostuffy or runny nose and sore throat (nasopharyngitis)opersistent cough (bronchitis)otrouble sleeping (insomnia)oleg or arm painodepressionoheadache (migraine)opain, redness, itching, or swelling at the site of injection (when given subcutaneously)These are not all the possible side effects of BENLYSTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store BENLYSTAoStore autoinjectors and prefilled syringes in the refrigerator at 36F to 46F (2C to 8C). Do not freeze.oKeep BENLYSTA autoinjectors and prefilled syringes in the original package until time of use to protect from light.oDo not shake. Keep away from heat and sunlight.oDo not use and do not place back in the refrigerator if left out at room temperature for more than 12 hours.oSafely throw away medicine that is out of date or no longer needed.Keep BENLYSTA and all medicines out of the reach of children.General information about the safe and effective use of BENLYSTA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use BENLYSTA for condition for which it was not prescribed. Do not give BENLYSTA to other people, even if they have the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important information about BENLYSTA. You can ask your healthcare provider or pharmacist for information about BENLYSTA that is written for healthcare professionals.What are the ingredients in BENLYSTAActive ingredient: belimumab.Inactive ingredients (intravenous): citric acid, polysorbate 80, sodium citrate, sucrose.Inactive Ingredients (subcutaneous): L-arginine hydrochloride, L-histidine, L-histidine monohydrochloride, polysorbate 80, sodium chloride.For more information, go to www.BENLYSTA.com or call 1-877-423-6597.Trademarks are owned by or licensed to the GSK group of companies.Manufactured by GlaxoSmithKline LLC Philadelphia, PA 19112, U.S. License No. 1727, andDistributed by GlaxoSmithKline Research Triangle Park, NC 27709(C)2021 GSK group of companies or its licensor.BNL:12MGThis Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2021. 1.Infections. Infections could be serious, leading to hospitalization or death. Tell your healthcare provider right away if you have any of the following symptoms of an infection:. ofever. ochills. opain or burning with urination. ourinating often. ocoughing up mucus. owarm, red, or painful skin or sores on your body. 2.Allergic (hypersensitivity) reactions. Serious allergic reactions can happen on the day of, or in the days after, receiving BENLYSTA and may cause death. Your healthcare provider will watch you closely while you are receiving BENLYSTA given intravenously (infusion) and after your infusion for signs of reaction. Allergic reactions can sometimes be delayed. Tell your healthcare provider right away if you have any of the following symptoms of an allergic reaction following use of BENLYSTA:. oitching. oswelling of the face, lips, mouth, tongue, or throat. otrouble breathing. oanxiousness. olow blood pressure. odizziness or fainting. oheadache. onausea. oskin rash. 3.Mental health problems and suicide. Symptoms of mental health problems can occur. Tell your healthcare provider right away if you have any of the following symptoms:. othoughts of suicide or dying. oattempt to commit suicide. otrouble sleeping (insomnia). onew or worse anxiety. onew or worse depression. oacting on dangerous impulses. oother unusual changes in your behavior or mood. othoughts of hurting yourself or others. oIt is not known if BENLYSTA is safe and effective in people with severe active central nervous system lupus.. oare allergic to belimumab or any of the ingredients in BENLYSTA. See the end of this Medication Guide for complete list of ingredients in BENLYSTA.. othink you have an infection or have infections that keep coming back. You should not receive BENLYSTA if you have an infection unless your healthcare provider tells you to. See What is the most important information should know about BENLYSTA. ohave or have had mental health problems such as depression or thoughts of suicide.. ohave recently received vaccination or if you think you may need vaccination. If you are receiving BENLYSTA, you should not receive live vaccines.. oare allergic to other medicines.. oare receiving other biologic medicines or monoclonal antibodies.. ohave or have had any type of cancer.. oare pregnant or plan to become pregnant. It is not known if BENLYSTA will harm your unborn baby. You should talk to your healthcare provider about whether to prevent pregnancy while on BENLYSTA. If you choose to prevent pregnancy, you should use an effective method of birth control while receiving BENLYSTA and for at least months after the final dose of BENLYSTA.oTell your healthcare provider right away if you become pregnant during your treatment with BENLYSTA or if you think you may be pregnant.. oTell your healthcare provider right away if you become pregnant during your treatment with BENLYSTA or if you think you may be pregnant.. oIf you become pregnant while receiving BENLYSTA, talk to your healthcare provider about enrolling in the BENLYSTA Pregnancy Registry. You can enroll in this registry by calling 1-877-681-6296. The purpose of this registry is to monitor the health of you and your baby.. oare breastfeeding or plan to breastfeed. It is not known if BENLYSTA passes into your breast milk. You and your healthcare provider should talk about whether or not you should receive BENLYSTA and breastfeed.. oYou will be given BENLYSTA by healthcare provider through needle placed in vein (IV infusion). It takes about hour to give you the full dose of BENLYSTA.. oYour healthcare provider will tell you how often you should receive BENLYSTA.. oYour healthcare provider may give you medicines before you receive BENLYSTA to help reduce your chance of having reaction. healthcare provider will watch you closely while you are receiving BENLYSTA and after your infusion for signs of reaction. healthcare provider will review the signs and symptoms of possible allergic reactions that could happen after your infusion.. oYour healthcare provider will tell you how often you should use BENLYSTA. Use BENLYSTA exactly as your healthcare provider tells you to.. oRead the Instructions for Use that comes with BENLYSTA for instructions about the right way to give your injections at home.. oBENLYSTA may be prescribed as single-dose autoinjector or as single-dose prefilled syringe.. oBefore you use BENLYSTA, your healthcare provider will show you or your caregiver how to give the injections and review the signs and symptoms of possible allergic reactions.. oBENLYSTA is injected under your skin (subcutaneously) of your stomach (abdomen) or thigh.. oUse BENLYSTA once week on the same day each week. If you have lupus nephritis, one dose may be injections.. oIf you miss your dose of BENLYSTA on your planned day, inject dose as soon as you remember. Then, inject your next dose at your regularly scheduled time or continue weekly dosing based on the new day injected. In case you are not sure when to inject BENLYSTA, call your healthcare provider.. oProgressive multifocal leukoencephalopathy (PML). PML is serious and life-threatening brain infection. Your chance of getting PML may be higher if you are treated with medicines that weaken your immune system, including BENLYSTA. PML can result in death or severe disability. If you notice any new or worsening medical problems such as those below, tell your healthcare provider right away:. omemory loss. otrouble thinking. odizziness or loss of balance. odifficulty talking or walking. oloss of vision. oCancer. BENLYSTA may reduce the activity of your immune system. Medicines that affect the immune system may increase your risk of certain cancers.. onausea. odiarrhea. ofever. ostuffy or runny nose and sore throat (nasopharyngitis). opersistent cough (bronchitis). otrouble sleeping (insomnia). oleg or arm pain. odepression. oheadache (migraine). opain, redness, itching, or swelling at the site of injection (when given subcutaneously). oStore autoinjectors and prefilled syringes in the refrigerator at 36F to 46F (2C to 8C). Do not freeze.. oKeep BENLYSTA autoinjectors and prefilled syringes in the original package until time of use to protect from light.. oDo not shake. Keep away from heat and sunlight.. oDo not use and do not place back in the refrigerator if left out at room temperature for more than 12 hours.. oSafely throw away medicine that is out of date or no longer needed.

SPL UNCLASSIFIED SECTION.

2.1 Intravenous Preparation and Dosing Instructions. Recommended Intravenous Dosage Regimen -- Adults with SLE or Lupus Nephritis and Pediatric Patients with SLEBENLYSTA for intravenous use must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus.The recommended intravenous dosage regimen is 10 mg/kg at 2-week intervals for the first doses and at 4-week intervals thereafter. Reconstitute, dilute, and administer as an intravenous infusion over period of hour. 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 serious hypersensitivity reaction [see Contraindications (4), Warnings and Precautions (5.2)].Premedication Recommendations prior to Intravenous UsePrior to intravenous dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions [see Warnings and Precautions (5.2, 5.3), Adverse Reactions (6.1)].Preparation of Intravenous SolutionsBENLYSTA for intravenous use is provided as lyophilized powder in single-dose vial and should be reconstituted and diluted by healthcare professional using aseptic technique as follows. Use of 21- to 25-gauge needle is recommended when piercing the vial stopper for reconstitution and dilution.Reconstitution Instructions for Intravenous Use:1.Remove the vial of BENLYSTA from the refrigerator and allow to stand for 10 to 15 minutes for the vial to reach room temperature.2.Reconstitute the BENLYSTA powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain concentration of 80 mg/mL belimumab.oReconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.oReconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP. 3.The stream of sterile water 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 during reconstitution, gently swirling the vial for 60 seconds every minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight.4.If mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.5.Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable.Dilution Instructions for Intravenous Use:1.Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), 0.45% Sodium Chloride Injection, USP (half-normal saline), or Lactated Ringers Injection, USP to volume of 250 mL for intravenous infusion. For patients whose body weight is less than or equal to 40 kg, 100 mL may be used such that the resulting belimumab concentration in the infusion bag does not exceed mg/mL. From 250-mL (or 100-mL) infusion bag or bottle of normal saline, half-normal saline, or Lactated Ringers Injection, withdraw and discard volume equal to the volume of the reconstituted solution of BENLYSTA required for the patients dose. Then add the required volume of the reconstituted solution of BENLYSTA 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.2.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.3.The reconstituted solution of BENLYSTA, if not used immediately, should be stored protected from direct sunlight and refrigerated at 36F to 46F (2C to 8C). Solutions of BENLYSTA diluted in normal saline, half-normal saline, or Lactated Ringers Injection may be stored at 36F to 46F (2C to 8C) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed hours.4.No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed.Administration Instructions for Intravenous Use1.The diluted solution of BENLYSTA should be administered by intravenous infusion over period of hour.2.BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis [see Warnings and Precautions (5.2)].3.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 coadministration of BENLYSTA with other agents.. 1.Remove the vial of BENLYSTA from the refrigerator and allow to stand for 10 to 15 minutes for the vial to reach room temperature.. 2.Reconstitute the BENLYSTA powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain concentration of 80 mg/mL belimumab.oReconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.oReconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP. oReconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.. oReconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.. 3.The stream of sterile water 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 during reconstitution, gently swirling the vial for 60 seconds every minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight.. 4.If mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.. 5.Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable.. 1.Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), 0.45% Sodium Chloride Injection, USP (half-normal saline), or Lactated Ringers Injection, USP to volume of 250 mL for intravenous infusion. For patients whose body weight is less than or equal to 40 kg, 100 mL may be used such that the resulting belimumab concentration in the infusion bag does not exceed mg/mL. From 250-mL (or 100-mL) infusion bag or bottle of normal saline, half-normal saline, or Lactated Ringers Injection, withdraw and discard volume equal to the volume of the reconstituted solution of BENLYSTA required for the patients dose. Then add the required volume of the reconstituted solution of BENLYSTA 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.. 2.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.. 3.The reconstituted solution of BENLYSTA, if not used immediately, should be stored protected from direct sunlight and refrigerated at 36F to 46F (2C to 8C). Solutions of BENLYSTA diluted in normal saline, half-normal saline, or Lactated Ringers Injection may be stored at 36F to 46F (2C to 8C) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed hours.. 4.No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed.. 1.The diluted solution of BENLYSTA should be administered by intravenous infusion over period of hour.. 2.BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis [see Warnings and Precautions (5.2)].. 3.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 coadministration of BENLYSTA with other agents.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BENLYSTA during pregnancy. Healthcare professionals are encouraged to register patients by calling 1-877-681-6296.Risk SummaryAvailable data on use of BENLYSTA in pregnant women, from observational studies, published case reports, and postmarketing surveillance, are insufficient to determine whether there is drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with SLE (see Clinical Considerations). Monoclonal antibodies, such as belimumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero-exposed infant (see Clinical Considerations). In an animal combined embryo-fetal and pre- and post-natal development study with monkeys that received belimumab by intravenous administration, there was no evidence of fetal harm with exposures approximately times (based on intravenous administration) and 20 times (based on subcutaneous administration) the exposure at the maximum recommended human dose (MRHD). Belimumab-related findings in monkey fetuses and/or infants included reductions of B-cell counts, reductions in the density of lymphoid tissue B-lymphocytes in the spleen and lymph nodes, and altered IgG and IgM titers. The no-adverse-effect-level (NOAEL) was not identified for these findings; however, they were reversible within to 12 months after the drug was discontinued (see Data). Based on animal data and the mechanism of action of belimumab, the immune system in infants of treated mothers may be adversely affected. It is unknown, based on available data, whether immune effects, if identified, are reversible [see Clinical Pharmacology (12.1)]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with SLE are at increased risk of adverse pregnancy outcomes, including worsening of the underlying disease, premature birth, miscarriage, and intrauterine growth restriction. Maternal lupus nephritis increases the risk of hypertension and preeclampsia/eclampsia. Passage of maternal autoantibodies across the placenta may result in adverse neonatal outcomes, including neonatal lupus and congenital heart block.Fetal/Neonatal Adverse Reactions: Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to BENLYSTA in utero. Monitor an infant of treated mother for B-cell reduction and other immune dysfunction [see Warnings and Precautions (5.6)]. DataAnimal Data: In combined embryo-fetal and pre- and post-natal development study, pregnant cynomolgus monkeys received belimumab at intravenous doses of 0, 5, or 150 mg/kg every weeks from confirmation of pregnancy at Gestation Days (GD) 20 to 22, throughout the period of organogenesis (up to approximately GD 50), and continuing to either the day of scheduled cesarean section (GD 150 [late third trimester]) or the day of parturition. There was no evidence of maternal toxicity, effects on embryofetal and infant survival, or structural abnormalities at exposure approximately times the MRHD of 10 mg/kg intravenously or 20 times the MRHD of 200 mg subcutaneously (on an AUC basis with maternal animal intravenous doses up to 150 mg/kg). Belimumab-related findings in mothers included reductions of immature and mature B-cell counts and in fetuses and/or infants included reductions of immature and mature B-cell counts, reductions in the density of lymphoid tissue B-lymphocytes in the spleen and lymph nodes, reduced spleen weights, increased IgG titers, and reduced IgM titers. B-cell counts in infant monkeys exposed to belimumab in utero recovered by months of age and in mothers after year. IgG and IgM levels in infant monkeys recovered by months of age and the reductions in B-lymphocytes in the lymph nodes and spleen were reversed by year of age. Belimumab crossed the placenta, as it was detected in fetal cord blood and amniotic fluid on GD 150.. 8.2 Lactation Risk SummaryNo information is available on the presence of belimumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Belimumab was detected in the milk of cynomolgus monkeys; however, due to species-specific differences in lactation physiology, animal data may not predict drug levels in human milk. Maternal IgG is known to be present in human milk. If belimumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to belimumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of BENLYSTA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BENLYSTA, and any potential adverse effects on the breastfed child from BENLYSTA or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential ContraceptionFollowing an assessment of benefit versus risk, if prevention of pregnancy is warranted, females of reproductive potential should use effective contraception during treatment and for at least months after the final treatment.. 8.4 Pediatric Use. Intravenous administration of BENLYSTA in patients with SLE is indicated in children aged years and older. Determination of efficacy in pediatric patients was based on pharmacokinetic (PK) and efficacy results from pediatric SLE study (Trial 6), as well as PK exposure and extrapolation of the established efficacy of BENYLSTA plus standard therapy from the Phase intravenous studies in adults with SLE. randomized, double-blind, placebo-controlled, PK, efficacy, and safety study (Trial 6) to evaluate intravenously administered BENLYSTA 10 mg/kg plus standard therapy compared with placebo plus standard therapy over 52 weeks was conducted in 93 pediatric patients with SLE. The proportion of pediatric patients achieving an SRI-4 response was higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. Pediatric patients receiving BENLYSTA plus standard therapy also had lower risk of experiencing severe flare compared with placebo plus standard therapy [see Clinical Studies (14.3)].The adverse event profile in pediatric patients was consistent with the overall population in the Phase studies in adults [see Adverse Reactions (6.1)].Pharmacokinetics were evaluated in total of 53 pediatric patients and were consistent with the adult population [see Clinical Pharmacology (12.3)]. The safety and effectiveness of BENLYSTA have not been established in pediatric patients younger than years of age.The safety and effectiveness of intravenous administration of BENLYSTA have not been established in pediatric patients with active lupus nephritis younger than 18 years of age.The safety and effectiveness of subcutaneous administration of BENLYSTA have not been established in pediatric patients younger than 18 years of age.. 8.5 Geriatric Use. Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects. Use with caution in elderly patients.. 8.6 Renal Impairment The safety and efficacy of BENLYSTA were evaluated in studies that included patients with SLE who had 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. No dosage adjustment is recommended in patients with renal impairment.. 8.7 Hepatic Impairment No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. No dosage adjustment is recommended in patients with hepatic impairment.. 8.8 Racial Groups. In Trial and Trial (intravenous dosing), SLE Responder Index-4 (SRI-4) response rates were lower for Black patients receiving BENLYSTA plus standard therapy relative to Black patients receiving placebo plus standard therapy [see Clinical Studies (14.1)].In Trial (intravenous dosing), 2:1 randomized, placebo-controlled trial in Black patients, SLE Responder Index (SRI-S2K) response rates were higher for Black patients receiving BENLYSTA plus standard therapy (49%) relative to Black patients receiving placebo plus standard therapy (42%). However, the treatment difference was not statistically significant [see Clinical Studies (14.1)].In Trial (subcutaneous dosing), SRI-4 response was 45% (26/58) in Black patients receiving BENLYSTA plus standard therapy compared with 39% (13/33) in Black patients receiving placebo plus standard therapy [see Clinical Studies (14.4)].The safety profile of BENLYSTA in Black patients was consistent with the known safety profile of BENLYSTA administered in the overall population [see Adverse Reactions (6.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSerious Infections: Serious and sometimes fatal infections have occurred in patients receiving immunosuppressive agents, including BENLYSTA. Use with caution in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA if patients develop new infection during treatment with BENLYSTA. (5.1)oProgressive Multifocal Leukoencephalopathy (PML): Evaluate patients with new-onset or deteriorating neurological signs and symptoms for PML. If confirmed, consider discontinuation of immunosuppressant therapy, including BENLYSTA. (5.1)oHypersensitivity Reactions, including Anaphylaxis: Serious and fatal reactions have been reported. BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis. Monitor patients during infusion and for an appropriate period of time after intravenous administration of BENLYSTA. (2.1, 5.2)oDepression and Suicidality: Depression and suicidality have been reported in trials with BENLYSTA. Assess for depression and risk of suicide before treatment with BENLYSTA and monitor during treatment. Instruct patients to contact their healthcare provider if new or worsening depression, suicidal thoughts, or other mood changes occur. (5.4)oImmunization: Live vaccines should not be given concurrently with BENLYSTA. (5.6). oSerious Infections: Serious and sometimes fatal infections have occurred in patients receiving immunosuppressive agents, including BENLYSTA. Use with caution in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA if patients develop new infection during treatment with BENLYSTA. (5.1). oProgressive Multifocal Leukoencephalopathy (PML): Evaluate patients with new-onset or deteriorating neurological signs and symptoms for PML. If confirmed, consider discontinuation of immunosuppressant therapy, including BENLYSTA. (5.1). oHypersensitivity Reactions, including Anaphylaxis: Serious and fatal reactions have been reported. BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis. Monitor patients during infusion and for an appropriate period of time after intravenous administration of BENLYSTA. (2.1, 5.2). oDepression and Suicidality: Depression and suicidality have been reported in trials with BENLYSTA. Assess for depression and risk of suicide before treatment with BENLYSTA and monitor during treatment. Instruct patients to contact their healthcare provider if new or worsening depression, suicidal thoughts, or other mood changes occur. (5.4). oImmunization: Live vaccines should not be given concurrently with BENLYSTA. (5.6). 5.1 Serious Infections. Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Overall, the incidence of serious infections in controlled trials was similar in patients receiving BENLYSTA compared with placebo, whereas fatal infections occurred more frequently in patients receiving BENLYSTA.In controlled trials of BENLYSTA administered intravenously in adults with SLE, the incidence of serious infections was 6.0% in patients receiving BENLYSTA compared with 5.2% in patients receiving placebo. The most frequent serious infections included pneumonia, urinary tract infections, cellulitis, and bronchitis. Fatal infections occurred in 0.3% of patients receiving BENLYSTA and in 0.1% of patients receiving placebo [see Adverse Reactions 6.1)].In controlled trial of active lupus nephritis, adults received BENLYSTA administered intravenously plus standard therapy or placebo plus standard therapy. Serious infections occurred in 14% of patients receiving BENLYSTA and in 17% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving BENLYSTA and in 0.9% (2/224) of patients receiving placebo [see Adverse Reactions 6.1)].In postmarketing safety trial of BENLYSTA administered intravenously to adults with SLE, the incidence of serious infections was 3.7% in patients receiving BENLYSTA compared with 4.1% in patients receiving placebo. Fatal infections occurred in 0.45% of patients receiving BENLYSTA and 0.15% of patients receiving placebo [see Adverse Reactions 6.1)].In controlled trial of BENLYSTA administered subcutaneously in adults with SLE, the incidence of serious infections was 4.1% in patients receiving BENLYSTA and 5.4% in patients receiving placebo. Fatal infections occurred in 0.5% of patients receiving BENLYSTA and in none of the patients receiving placebo [see Adverse Reactions 6.2)].Consider the risk and benefit before initiating treatment with BENLYSTA in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA in patients who develop new infection while receiving it and monitor these patients closely.Progressive Multifocal Leukoencephalopathy (PML)Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with neurologist or other appropriate specialist as clinically indicated. In patients with confirmed PML, consider stopping immunosuppressant therapy, including BENLYSTA.. 5.2 Hypersensitivity Reactions, including Anaphylaxis. Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema have been reported and typically occurred up to week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with history of multiple drug allergies or significant hypersensitivity may be at increased risk.In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.3)]. Some patients (13%) received premedication, which may have mitigated or masked hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.In controlled trial of BENLYSTA administered subcutaneously in adults with SLE, systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials.BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis. In the event of serious reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Monitor patients during infusion and for an appropriate period of time after intravenous administration of BENLYSTA. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration (2.1)]. Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should reaction occur.. 5.3 Infusion Reactions. In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (>=3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.2)]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration (2.1), Adverse Reactions (6.1)].BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely [see Warnings and Precautions (5.2)].. 5.4 Depression and Suicidality. In controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, psychiatric events were reported more frequently in patients treated with BENLYSTA (16%) than with placebo (12%) and were related primarily to depression-related events, insomnia, and anxiety. Serious psychiatric events and serious depression were reported in 0.8% and 0.4% of patients receiving BENLYSTA, and 0.4% and 0.1% of patients receiving placebo, respectively. Two suicides (0.1%) were reported in patients receiving BENLYSTA (one with 10 mg/kg and one with mg/kg) [see Adverse Reactions 6.1)].In postmarketing trial of BENLYSTA administered intravenously in adults with SLE, serious psychiatric events and serious depression were reported in 1.0% and 0.3% of patients receiving BENLYSTA, and 0.3% and <0.1% of patients receiving placebo, respectively. The overall incidence of suicidal ideation or behavior or self-injury without suicidal intent was 0.7% of patients receiving BENLYSTA and 0.2% of patients receiving placebo. No suicide was reported in either group [see Adverse Reactions 6.1)].The intravenous trials above did not exclude patients with history of psychiatric disorders.In controlled trial of BENLYSTA administered subcutaneously in adults with SLE, which excluded patients with history of psychiatric disorders, psychiatric events were reported less frequently in patients receiving BENLYSTA (6%) compared with those receiving placebo (11%). There were no serious depression-related events or suicides reported in either group [see Adverse Reactions 6.2)].Assess the risk of depression and suicide considering the patients medical history and current psychiatric status before treatment with BENLYSTA and continue to monitor patients during treatment. Instruct patients receiving BENLYSTA (and caregivers, if applicable) to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or behavior, or other mood changes. Consider the risk and benefit of continued treatment with BENLYSTA for patients who develop such symptoms.. 5.5 Malignancy. The impact of treatment with BENLYSTA on the development of malignancies is not known.In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the intravenous controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. In controlled clinical trial of BENLYSTA administered subcutaneously in adults with SLE (N 836), the data were similar. The mechanism of action of BENLYSTA could increase the risk for the development of malignancies.. 5.6 Immunization. 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 or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.. 5.7 Concomitant Use with Other Biologic Therapies BENLYSTA has not been studied in combination with other biologic therapies, including B-cell-targeted therapies. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies.