Benlysta Drug Information

Generic name: BELIMUMAB

B Lymphocyte Stimulator-specific Inhibitor [EPC]

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Uses of Benlysta

  • is indicated for the treatment of patients 5 years of age and older with:
  • Active systemic lupus erythematosus (SLE) who are receiving standard therapy, and
  • Active lupus nephritis who are receiving standard therapy. Limitations of Use The efficacy of BENLYSTA has not been evaluated in patients with severe active central nervous system (CNS) lupus. Use of BENLYSTA is not recommended in this situation. BENLYSTA is a B-lymphocyte stimulator (BLyS)-specific inhibitor indicated for the treatment of patients 5 years of age and older with:
  • Active systemic lupus erythematosus (SLE) who are receiving standard therapy; ( 1 )
  • Active lupus nephritis who are receiving standard therapy. ( 1 ) Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active central nervous system lupus. Use of BENLYSTA is not recommended in this situation. ( 1 )

Dosage & Administration of Benlysta

a Prefilled syringe has not been studied in children less than 18 years of age.
b The 400-mg dose requires administration of two 200‑mg injections.
IndicationAdults (Autoinjector or Prefilled Syringe)
Active SLE200 mg once weekly
Active Lupus Nephritis400 mgb once weekly for 4 doses, followed by 200 mg once weekly

Side Effects of Benlysta

  • The following serious adverse reactions are described below and in the Warnings and Precautions section:
  • Serious Infections [see Warnings and Precautions ( 5.1 )]
  • Hypersensitivity Reactions, including Anaphylaxis [see Warnings and Precautions ( 5.2 )]
  • Depression and Suicidality [see Warnings and Precautions ( 5.3 )]
  • Malignancy [see Warnings and Precautions ( 5.4 )] Common adverse reactions (≥5%): nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, pharyngitis, and injection site reactions (subcutaneous administration). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-877-423-6597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Intravenous Administration in Adult Subjects with Active SLE The data described in Table 2 reflect exposure to BENLYSTA administered intravenously plus standard therapy compared with placebo plus standard therapy in 2,133 adult subjects with active SLE in 3 controlled trials (Trials 1, 2, and 3). Subjects received BENLYSTA plus standard therapy at doses of 1 mg/kg (n = 673), 4 mg/kg (n = 111; Trial 1 only), or 10 mg/kg (n = 674), or placebo plus standard therapy (n = 675) intravenously over a 1‑hour period on Days 0, 14, 28, and then every 28 days. In 2 of the trials (Trial 1 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 ( 14.2 )] . 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 3 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. In Trials 1, 2, and 3, 93% of subjects 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% and 5.2% in the groups receiving BENLYSTA and placebo plus standard therapy, respectively), some of which were fatal. The most commonly reported adverse events, occurring in ≥5% of subjects in Trials 1, 2, and 3 were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis. The proportion of subjects who discontinued treatment due to any adverse reaction during Trials 1, 2, and 3 was 6.2% for subjects receiving BENLYSTA plus standard therapy and 7.1% for subjects receiving placebo plus standard therapy. The most common adverse reactions resulting in discontinuation of treatment (≥1% of subjects 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% placebo). Table 2 lists adverse reactions, regardless of causality, occurring in at least 3% of subjects with active 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 3 controlled trials (Trials 1, 2, and 3). Table 2. Incidence of Adverse Reactions Occurring in at Least 3% of Adult Subjects with Active SLE Treated with BENLYSTA 10 mg/kg plus Standard Therapy and at Least 1% More Frequently than in Subjects Receiving Placebo plus Standard Therapy (Trials 1, 2, and 3) Adverse Reactions BENLYSTA 10 mg/kg + Standard Therapy (n = 674) % Placebo + Standard Therapy (n = 675) % Nausea 15 12 Diarrhea 12 9 Pyrexia 10 8 Nasopharyngitis 9 7 Bronchitis 9 5 Insomnia 7 5 Pain in extremity 6 4 Depression 5 4 Migraine 5 4 Pharyngitis 5 3 Cystitis 4 3 Leukopenia 4 2 Gastroenteritis viral 3 1 Specific Adverse Reactions in Adult Subjects with Active SLE (Intravenous Administration) Infections: In Trials 1, 2, and 3, the overall incidence of infections was 71% in subjects receiving BENLYSTA compared with 67% in subjects receiving placebo. The most frequent infections (>5% of subjects 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 subjects receiving BENLYSTA and 1.0% of subjects receiving placebo. Serious Infections: In Trials 1, 2, and 3, the incidence of serious infections was 6.0% in subjects receiving BENLYSTA and 5.2% in subjects receiving placebo. The most frequent serious infections included pneumonia, urinary tract infections, cellulitis, and bronchitis. Fatal infections occurred in 0.3% (4/1,458) of subjects receiving BENLYSTA and in 0.1% (1/675) of subjects receiving placebo. In a randomized, double‑blind, placebo‑controlled, 52‑week, postmarketing safety trial of BENLYSTA administered intravenously in adults with active SLE (N = 4,003), the incidence of serious infections was 3.7% in subjects receiving BENLYSTA compared with 4.1% in subjects receiving placebo. Serious infections leading to discontinuation of treatment occurred in 1.0% of subjects receiving BENLYSTA and in 0.9% of subjects receiving placebo. Fatal infections occurred in 0.45% (9/2,002) of subjects receiving BENLYSTA and in 0.15% (3/2,001) of subjects receiving placebo, where the incidence of all‑cause mortality was 0.50% (10/2,002) in subjects receiving BENLYSTA and 0.40% (8/2,001) in subjects receiving placebo. Hypersensitivity Reactions, including Anaphylaxis: In Trials 1, 2, and 3, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of subjects receiving BENLYSTA and 11% (76/675) of subjects receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of subjects receiving BENLYSTA and 0.4% (3/675) of subjects receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Infusion ‑ Related Reactions: In Trials 1, 2, and 3, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of subjects receiving BENLYSTA and 15% (99/675) of subjects receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of subjects receiving BENLYSTA and 0.4% of subjects receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥3% of subjects receiving BENLYSTA) were headache, nausea, and skin reactions. Depression and Suicidality: In Trials 1, 2, and 3, 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% BENLYSTA; 5.3% placebo), and anxiety (3.9% BENLYSTA; 2.8% placebo). Serious psychiatric events were reported in 0.8% (12/1,458) of subjects receiving BENLYSTA and 0.4% (3/675) of subjects receiving placebo. Serious depression was reported in 0.4% (6/1,458) of subjects receiving BENLYSTA and 0.1% (1/675) of subjects receiving placebo. Two suicides (0.1%) were reported in subjects receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg). In a 52‑week postmarketing safety trial of BENLYSTA (N = 4,003), serious psychiatric events were reported in 1% (20/2,002) of subjects receiving BENLYSTA and 0.3% (6/2,001) of subjects receiving placebo. Serious depression was reported in 0.3% (7/2,002) of subjects 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 subjects receiving BENLYSTA and 0.2% (5/2,001) of subjects receiving placebo. On the Columbia‑Suicide Severity Rating Scale (C‑SSRS), 2.4% (48/1,974) of subjects receiving BENLYSTA reported suicidal ideation or behavior compared with 2% (39/1,988) of subjects receiving placebo. No suicide was reported in either group. The intravenous trials above did not exclude subjects with a history of psychiatric disorders. Malignancy: In Trials 1, 2, and 3, malignancies (including non‑melanoma skin cancers) were reported in 0.4% of subjects receiving BENLYSTA and 0.4% of subjects 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 subjects receiving BENLYSTA and placebo, respectively. Intravenous Administration in Black/African ‑ American Subjects with Active SLE The safety of BENLYSTA 10 mg/kg administered intravenously in adults plus standard therapy (n = 331) compared with placebo plus standard therapy (n = 165) in Black subjects with active SLE (Trial 4) was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in the overall population [see Clinical Studies ( 14.2 )] . Intravenous Administration in Adult Subjects with Active 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 ( 14.3 )] . The adverse reactions observed were consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in patients with active 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. Specific Adverse Reactions in Adult Subjects with Active Lupus Nephritis (Intravenous Administration) Infections: In Trial 5, the overall incidence of infections was 82% in subjects receiving BENLYSTA compared with 76% in subjects receiving placebo. Serious Infections: In Trial 5, serious infections occurred in 14% of subjects receiving BENLYSTA and in 17% of subjects receiving placebo. Fatal infections occurred in 0.9% (2/224) of subjects receiving BENLYSTA and in 0.9% (2/224) of subjects receiving placebo. Intravenous Administration in Pediatric Subjects 5 Years of Age and Older with Active SLE The safety of BENLYSTA administered intravenously plus standard therapy (n = 53) compared with placebo plus standard therapy (n = 40) was evaluated in 93 pediatric subjects with active SLE (Trial 6). The adverse reactions observed were consistent with those observed in adults with SLE [see Clinical Studies ( 14.4 )] . Subcutaneous Administration in Adult Subjects with Active SLE The data described below reflect exposure to BENLYSTA administered subcutaneously plus standard therapy compared with placebo plus standard therapy in 836 adult subjects with active SLE in a controlled trial (Trial 7). In addition to standard therapy, subjects received BENLYSTA 200 mg (n = 556) or placebo (n = 280) (2:1 randomization) once weekly for up to 52 weeks [see Clinical Studies ( 14.5 )] . In the trial, 81% of subjects treated with BENLYSTA plus standard therapy reported an adverse event compared with 84% treated with placebo plus standard therapy. The proportion of subjects who discontinued treatment due to any adverse reaction during the controlled clinical trial was 7.2% of subjects receiving BENLYSTA plus standard therapy and 8.9% of subjects 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. Infections: In Trial 7, the overall incidence of infections was 55% in subjects receiving BENLYSTA compared with 57% in subjects receiving placebo. The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously. Serious Infections: In Trial 7, the incidence of serious infections was 4.1% in subjects receiving BENLYSTA and 5.4% in subjects receiving placebo. Fatal infections occurred in 0.5% (3/556) of subjects receiving BENLYSTA and in none of the subjects receiving placebo (0/280). Depression and Suicidality: In Trial 7, which excluded subjects with a history of psychiatric disorders, psychiatric events were reported in 6% of subjects receiving BENLYSTA and 11% of subjects receiving placebo. Depression‑related events were reported in 2.7% (15/556) of subjects receiving BENLYSTA and 3.6% (10/280) of subjects receiving placebo. Serious psychiatric events were reported in 0.2% (1/556) of subjects receiving BENLYSTA and in no subjects receiving placebo. There were no serious depression‑related events or suicides reported in either group. On the C‑SSRS, 1.3% (7/554) of subjects receiving BENLYSTA reported suicidal ideation or behavior compared with 0.7% (2/277) of subjects receiving placebo. Malignancy: In Trial 7, the reports of malignancies were similar to those reported with BENLYSTA administered intravenously. Injection Site Reactions: In Trial 7, the frequency of injection site reactions was 6.1% (34/556) for subjects receiving BENLYSTA plus standard therapy and 2.5% (7/280) for subjects 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. Concomitant Use of Subcutaneous BENLYSTA and Intravenous Rituximab in Adult Subjects with Active SLE BENLYSTA administered subcutaneously in combination with intravenous rituximab was studied in a Phase 3, randomized, double‑blind, placebo‑controlled, 104‑week trial in adult subjects with active SLE. Subjects were randomized to 1 of the 3 treatment arms: BENLYSTA with a single cycle of rituximab (n = 144); BENLYSTA with placebo (n = 72); BENLYSTA plus standard therapy (n = 76). In general, adverse reactions were consistent with the known safety profile of BENLYSTA and rituximab. When compared with BENLYSTA and placebo or BENLYSTA plus standard therapy, BENLYSTA in combination with rituximab was associated with higher frequency of serious adverse events (13.9%, 19.7%, 22.2%, respectively), serious infections (2.8%, 5.3%, 9.0%, respectively), and post‑injection systemic reactions (9.7%, 5.3%, 13.2%, respectively). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BENLYSTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
  • Fatal anaphylaxis [see Warnings and Precautions ( 5.2 )].

Warnings & Cautions for Benlysta

  • Serious 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 a new infection during treatment with BENLYSTA. ( 5.1 )
  • Progressive Multifocal Leukoencephalopathy (PML): Evaluate patients with new-onset or deteriorating neurological signs and symptoms for PML. If PML is suspected, immunosuppressant therapy, including BENLYSTA, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including BENLYSTA, must be discontinued. ( 5.1 )
  • Hypersensitivity Reactions, including Anaphylaxis: Serious and fatal reactions have been reported. ( 5.2 )
  • Depression and Suicidality: Depression and suicidality were 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. ( 5.3 )
  • Immunization: Live vaccines should not be given concurrently with BENLYSTA. ( 5.5 ) 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 subjects receiving BENLYSTA compared with placebo, whereas fatal infections occurred more frequently in subjects receiving BENLYSTA [see Adverse Reactions ( 6.1 )] . 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 a 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 a neurologist or other appropriate specialist as clinically indicated. In patients with suspected PML, immunosuppressant therapy, including BENLYSTA, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including BENLYSTA, must be discontinued. 5.2 Hypersensitivity Reactions, including Anaphylaxis Acute hypersensitivity reactions, including anaphylaxis and death, and infusion-related reactions have been reported in association with BENLYSTA [see Adverse Reactions ( 6.1 )] . 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 a 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 a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion-related reactions in all cases. In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, some subjects (13%) received premedication, which may have mitigated or masked a hypersensitivity response or infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions or infusion-related reaction. BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis and infusion-related reactions. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion-related reactions. In the event of a serious reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. With intravenous administration, the infusion rate may be slowed or interrupted if the patient develops an infusion reaction. 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 , 2.2 )] . Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should a reaction occur. 5.3 Depression and Suicidality In controlled clinical trials, depression and suicidality were reported in subjects receiving BENLYSTA [see Adverse Reactions ( 6.1 )] . Assess the risk of depression and suicide considering the patient’s medical history and current psychiatric status before treatment with BENLYSTA and continue to monitor patients during treatment. 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. 5.4 Malignancy There is an increased risk of malignancies with the use of immunosuppressants. The impact of treatment with BENLYSTA on the development of malignancies is not known [see Adverse Reactions ( 6.1 )] . Consider the individual benefit-risk in patients with known risk factors for the development or reoccurrence of malignancy prior to prescribing BENLYSTA. In patients who develop malignancies, consider the risk and benefit of continued treatment with BENLYSTA. 5.5 Immunization Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations. 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. 5.6 Concomitant Use with Other Biologic Therapies Available data do not support the safety and efficacy of concomitant use of BENLYSTA with rituximab in patients with SLE. An increased incidence of serious infections and post-injection systemic reactions in subjects receiving BENLYSTA concomitantly with rituximab compared to subjects receiving BENLYSTA alone has been observed [see Adverse Reactions ( 6.1 )] . The safety and efficacy of BENLYSTA concomitantly with other biologic therapies, including B-cell-targeted therapies, have not been established. Caution should be exercised if BENLYSTA is administered in combination with other biologic therapies [see Warnings and Precautions ( 5 )] .

Drug Interactions with Benlysta

Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, cyclophosphamide, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG‑CoA reductase inhibitors (statins), and/or non-steroidal anti-inflammatory drugs (NSAIDs) without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated .

Pregnancy Safety for Benlysta

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that evaluates pregnancy outcomes in women with lupus exposed to BENLYSTA during pregnancy. Healthcare professionals are encouraged to refer patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/benlysta-belimumab/. Risk Summary Available data on use of BENLYSTA in pregnant women, from observational studies, published case reports, and postmarketing surveillance, are insufficient to determine whether there is a 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 9 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 3 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 . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 Considerations Disease-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 a treated mother for B-cell reduction and other immune dysfunction . Data Animal Data: In a 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 2 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 ) or the day of parturition. There was no evidence of maternal toxicity, effects on embryofetal and infant survival, or structural abnormalities at exposure approximately 9 times the MRHD of 10 mg/kg intravenously or 20 times the MRHD of 200 mg subcutaneously (on an area under the curve 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 3 months of age and in mothers after 1 year.

Immunoglobulin G (IgG) and IgM levels in infant monkeys recovered by 6 months of age and the reductions in B-lymphocytes in the lymph nodes and spleen were reversed by 1 year of age. Belimumab crossed the placenta, as it was detected in fetal cord blood and amniotic fluid on GD 150.

Pediatric Use of Benlysta

Pediatric Use The safety and effectiveness of BENLYSTA have been established for the treatment of active SLE and active lupus nephritis in pediatric patients 5 years of age and older who are receiving standard therapy. The safety and effectiveness of BENLYSTA have not been established in pediatric patients less than 5 years of age. Intravenous Use Use of BENLYSTA intravenously in pediatric patients 5 years of age and older with active SLE is supported by evidence from pharmacokinetic (PK), safety, and efficacy results from a pediatric trial (Trial 6), as well as PK exposure and extrapolation of the established efficacy of BENLYSTA plus standard therapy from the Phase 3 intravenous studies in adults with active SLE (Trials 2 and 3). In Trial 6, the proportion of pediatric subjects achieving an SRI‑4 response was higher in subjects receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy.

Pediatric subjects receiving BENLYSTA plus standard therapy also had a lower risk of experiencing a severe flare compared with placebo plus standard therapy . Pharmacokinetics were evaluated in a total of 53 pediatric subjects (Trial 6) and were consistent with the adult population with active SLE . Use of BENLYSTA intravenously in pediatric patients 5 years of age and older with active lupus nephritis is based on the extrapolation of efficacy from the intravenous trial (Trial 5) in adults (n = 224) with active lupus nephritis, and supported by pharmacokinetic data from intravenous studies in adults (n = 224) with active lupus nephritis and from pediatric subjects (n = 53) with active SLE (Trial 6). Estimated belimumab exposures for pediatric patients were comparable to adults with active lupus nephritis . Subcutaneous Use Use of BENLYSTA, administered subcutaneously in pediatric patients 5 years of age and older who weigh at least 15 kg with active SLE, is supported by evidence from an open‑label pharmacokinetic trial (subcutaneous administration of BENLYSTA in pediatric subjects with active SLE) and Trial 6 (a pharmacokinetic, efficacy, and safety trial of intravenous dosing in pediatric subjects with active SLE). The pharmacokinetics of belimumab, following subcutaneous administration in pediatric patients, are estimated to be comparable to adults who receive BENLYSTA subcutaneously and pediatric patients who receive BENLYSTA intravenously . Use of BENLYSTA, administered subcutaneously in pediatric patients 5 years of age and older who weigh at least 15 kg with active lupus nephritis, is based on the extrapolation of efficacy from the intravenous trial in adults (n = 224) with active lupus nephritis (Trial 5), and is supported by pharmacokinetic data derived from the same adult trial (Trial 5), a pharmacokinetic, efficacy, and safety intravenous trial in pediatric subjects with active SLE (n = 53) (Trial 6), and an open‑label subcutaneous trial in pediatric subjects with active SLE (n = 25). Belimumab exposures for pediatric patients with active lupus nephritis following subcutaneous administration are estimated to be comparable to adults with active lupus nephritis who receive BENLYSTA intravenously .

Contraindications for Benlysta

is contraindicated in patients who have had anaphylaxis with belimumab. Previous anaphylaxis to belimumab.

Overdosage Information for Benlysta

There is limited experience with overdosage of belimumab. Two doses of up to 20 mg/kg have been given intravenously to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

Clinical Studies of Benlysta

  • 14.1 Overview of Clinical Trials The safety and effectiveness of BENLYSTA administered:
  • Intravenously plus standard therapy were evaluated in 4 randomized, double‑blind, placebo‑controlled trials with 2,581 adult subjects with active SLE (Trial 1, NCT00071487, Trial 2, NCT00410384, Trial 3, NCT00424476, and Trial 4 NCT01632241) [see Clinical Studies ( 14.2 )] , and one randomized, double‑blind, placebo‑controlled trial with 93 pediatric subjects 5 years of age and older with active SLE (Trial 6, NCT01649765) [see Clinical Studies ( 14.4 )] , according to the American College of Rheumatology criteria. In these trials, subjects with severe active lupus nephritis and severe active CNS lupus were excluded. Subjects were on a 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.
  • Intravenously plus standard therapy were evaluated in a randomized, double‑blind, placebo‑controlled trial in 448 adult subjects with active lupus nephritis (Trial 5; NCT01639339) [see Clinical Studies ( 14.3 )] .
  • Subcutaneously plus standard therapy in adults were evaluated in a randomized, double‑blind, placebo‑controlled trial in 836 adult subjects with active SLE (Trial 7; NCT01484496) [see Clinical Studies ( 14.5 )]. 14.2 Intravenous Administration in Adults with Active SLE Trial 1: Active SLE – BENLYSTA 1 mg/kg, 4 mg/kg, 10 mg/kg - Intravenous Trial 1 enrolled 449 adult subjects and evaluated doses of 1, 4, and 10 mg/kg BENLYSTA plus standard therapy compared with placebo plus standard therapy over 52 weeks in subjects with SLE. Subjects had to have a Safety of Estrogens in Lupus Erythematosus National Assessment‑Systemic Lupus Erythematosus Disease Activity Index (SELENA‑SLEDAI) score of ≥4 at baseline and a 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 a subgroup of subjects (72%) who were autoantibody positive in whom BENLYSTA appeared to offer benefit. The results of this trial informed the design of Trials 2 and 3 and led to the selection of a target population limited to autoantibody‑positive SLE patients. Trials 2, 3, and 4: Active SLE – BENLYSTA 1 mg/kg and 10 mg/kg - Intravenous Trials 2 and 3 were randomized, double‑blind, placebo‑controlled trials in adult subjects with SLE that were similar in design except duration; Trial 2 (N = 819) was 76 weeks’ duration and Trial 3 (N = 865) was 52 weeks’ duration. Subjects had active SLE disease with a SELENA‑SLEDAI score ≥6 and positive autoantibody test results at screening. Subjects were excluded from the trial if they had ever received treatment with a B‑cell–targeted agent or if they were currently receiving other biologic agents. Intravenous cyclophosphamide was not permitted within the previous 6 months or during the trial. Trial 2 was conducted primarily in North America and Europe. Trial 3 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 subjects (>70%) were receiving 2 or more classes of SLE medications. In Trial 2 and Trial 3, more than 50% of subjects had 3 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 subjects had some degree of renal activity and less than 7% of subjects had activity in the vascular, cardio‑respiratory, or CNS systems. At screening, subjects were stratified by disease severity based on their SELENA‑SLEDAI score (≤9 vs. ≥10), proteinuria level (<2 g/24 h vs. ≥2 g/24 h), and race (African or Indigenous‑American descent vs. other), and then randomly assigned to receive BENLYSTA 1 mg/kg, BENLYSTA 10 mg/kg, or placebo in addition to standard therapy. The subjects were administered trial medication intravenously over a 1‑hour period on Days 0, 14, 28, and then every 28 days for 48 weeks in Trial 3 and for 72 weeks in Trial 2. The primary efficacy endpoint was a 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:
  • ≥4‑point reduction in the SELENA‑SLEDAI score, and
  • no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and
  • no worsening (<0.30‑point increase) in Physician’s Global Assessment (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 patient’s condition overall. In both Trials 2 and 3, the proportion of subjects 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 subjects receiving BENLYSTA 1 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 5 ). 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 5. Clinical Response Rate in Adult Subjects with Active SLE after 52 Weeks of Intravenous Treatment (Trials 2 and 3) a The 1-mg/kg dose is not recommended. b Subjects dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. In both trials, a higher proportion of placebo subjects were considered as failures for this reason compared with the groups receiving BENLYSTA. Response Trial 2 Trial 3 Placebo + Standard Therapy (n = 275) BENLYSTA 1 mg/kg + Standard Therapy a (n = 271) BENLYSTA 10 mg/kg + Standard Therapy (n = 273) Placebo + Standard Therapy (n = 287) BENLYSTA 1 mg/kg + Standard Therapy a (n = 288) BENLYSTA 10 mg/kg + Standard Therapy (n = 290) SLE Responder Index-4 (SRI-4) b 34% 41% P = 0.104 43% P = 0.021 44% 51% P = 0.013 58% P <0.001 Odds Ratio (95% CI) vs. placebo 1.3 (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 subjects with reduction in SELENA-SLEDAI ≥4 36% 43% 47% 46% 53% 58% Percent of subjects with no worsening by BILAG index 65% 75% 69% 73% 79% 81% Percent of subjects with no worsening by PGA 63% 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 Subjects: In Trials 2 and 3, exploratory sub‑group analyses of SRI-4 response rate in Black subjects (n = 148) were performed. The SRI‑4 response rate in Black subjects 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 1 mg/kg, and 18/50 or 36% for BENLYSTA 10 mg/kg). Trial 4 included 448 Black subjects and was conducted in North America, South America, Europe, and Africa. It had the same trial design as Trials 2 and 3 with exceptions of subjects having a baseline SELENA‑SLEDAI score of ≥8 and using the modified SLEDAI‑2K scoring for proteinuria. The population had a mean age of 39 years (range: 18 to 71) and 97% were female. The proportion of Black subjects 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 6 ). Table 6. Clinical Response Rate in Black Adult Subjects with Active SLE after 52 Weeks of Intravenous Treatment (Trial 4) a Analyses excluded any subject missing a baseline assessment for any of the components (1 for belimumab). b Subjects dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. A higher proportion of subjects receiving placebo were considered as failures for this reason compared with the group receiving BENLYSTA. Response a Placebo + Standard Therapy (n = 149) BENLYSTA 10 mg/kg + Standard Therapy (n = 298) SLE Responder Index (SRI-S2K) b 42% 49% Odds Ratio (95% CI) vs. placebo 1.4 (0.9, 2.1) P = 0.107 Components of SLE Responder Index (SRI-S2K) Percent of subjects with reduction in SELENA‑SLEDAI-S2K ≥4 42% 50% Odds Ratio (95% CI) vs. placebo 1.5 (1.0, 2.2) Percent of subjects with no worsening by BILAG index 62% 68% Odds Ratio (95% CI) vs. placebo 1.2 (0.8, 1.9) Percent of subjects with no worsening by PGA 64% 70% Odds Ratio (95% CI) vs. placebo 1.3 (0.8, 1.9) Effect on Concomitant Steroid Treatment: In Trial 2 and Trial 3, 46% and 69% of subjects, respectively, were receiving prednisone at doses >7.5 mg/day at baseline. The proportion of subjects 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 subjects receiving BENLYSTA 10 mg/kg plus standard therapy and 19% of subjects receiving BENLYSTA 1 mg/kg plus standard therapy achieved this level of steroid reduction compared with 13% of subjects receiving placebo plus standard therapy. In Trial 3, 19%, 21%, and 12% of subjects receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg, and placebo, respectively, plus standard therapy achieved this level of steroid reduction. Effect on Severe SLE Flares: The probability of experiencing a severe SLE flare, as defined by a 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 2 and 3. The proportion of subjects having at least 1 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 subjects receiving BENLYSTA 10 mg/kg plus standard therapy and 16% of subjects receiving BENLYSTA 1 mg/kg plus standard therapy had a severe flare compared with 24% of subjects receiving placebo plus standard therapy. In Trial 3, 14%, 18%, and 23% of subjects receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg and placebo, respectively, plus standard therapy had a severe flare. 14.3 Intravenous Administration in Adults with Active Lupus Nephritis Trial 5: Active Lupus Nephritis – BENLYSTA 10 mg/kg - Intravenous The safety and effectiveness of BENLYSTA 10 mg/kg administered intravenously over 1 hour on Days 0, 14, 28, and then every 28 days plus standard therapy were evaluated in a 104‑week, randomized, double‑blind, placebo‑controlled trial in 448 adult subjects with active proliferative and/or membranous lupus nephritis (Trial 5). The subjects had a 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 subjects 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 a response at Week 100 confirmed by a 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 m 2 or no decrease in eGFR of >20% from pre‑flare value. The major secondary endpoints included:
  • Complete Renal Response (CRR) defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: uPCR <0.5 g/g and eGFR ≥90 mL/min/1.73 m 2 or no decrease in eGFR of >10% from pre-flare value.
  • PERR at Week 52.
  • Time 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 subjects achieving PERR at Week 104 was significantly higher in subjects receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy ( Table 7 ). The major secondary endpoints also showed significant improvement with BENLYSTA plus standard therapy compared with placebo plus standard therapy ( Table 7 and Table 8 ). Table 7. Efficacy Results in Adult Subjects with Active Lupus Nephritis (Intravenous Treatment) (Trial 5) eGFR = Estimated glomerular filtration rate. a 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. b In order to be considered a responder, steroid treatment had to be reduced to ≤10 mg/day from Week 24. Subjects who discontinued treatment early, received prohibited medication or increases in background standard therapy, or withdrew from the trial 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, intravenous immunoglobulin (IVIG), or plasmapheresis. c The percentage of subjects 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. Efficacy Endpoint a Placebo + Standard Therapy n = 223 BENLYSTA + Standard Therapy n = 223 Odds Ratio (OR) vs. Placebo (95% CI) Primary Efficacy Renal Response (PERR) at Week 104 b,c (responders) 32% 43% 1.6 (1.0, 2.3) P = 0.031 Components of PERR Urine protein:creatinine ratio ≤0.7 g/g 34% 44% 1.5 (1.0, 2.3) eGFR ≥60 mL/min/1.73 m 2 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 104 b,c (responders) 20% 30% 1.7 (1.1, 2.7) P = 0.017 Components of CRR Urine protein:creatinine ratio <0.5 g/g 29% 39% 1.6 (1.1, 2.4) eGFR ≥90 mL/min/1.73 m 2 or no decrease in eGFR from pre-flare value of >10% 40% 47% 1.3 (0.9, 2.0) PERR at Week 52 b (responders) 35% 47% 1.6 (1.1, 2.4) P = 0.025 In 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 Subgroups a, b in Adult Subjects with Active Lupus Nephritis (Intravenous Treatment) (Trial 5) a Class III = Focal proliferative lupus nephritis; Class IV = Diffuse proliferative lupus nephritis; Class V = 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 a 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 Adult Subjects with Active Lupus Nephritis (+/- Standard Error) by Visit a (Intravenous Treatment) (Trial 5) a Analysis is descriptive; bars represent standard error. The same subjects may not have responded at each timepoint. In Trial 5, subjects who received BENLYSTA were significantly less likely to experience a renal-related event or death compared with placebo ( Table 8 ). Table 8. Time to RenalRelated Event or Death a in Adult Subjects with Active Lupus Nephritis (Intravenous Treatment) (Trial 5) Placebo + Standard Therapy n = 223 BENLYSTA + Standard Therapy n = 223 Hazard Ratio (HR) vs. Placebo (95% CI) a Time to renal-related event or death included in pre-specified testing hierarchy. b When excluding deaths from analysis (1 for BENLYSTA; 2 for placebo), the percentage of subjects with a renal-related event was 15% for BENLYSTA compared with 27% for placebo (HR = 0.5; 95% CI: 0.3, 0.8). c Subjects who discontinued treatment, were withdrawn from the trial, lost to follow-up, or had a 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 1 day). d Subjects could have had more than one event; the first event contributed to the overall endpoint. e Renal worsening was prospectively defined as the development of increased proteinuria and/or impaired renal function defined as: 1) Increased proteinuria (using spot urine): a 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 1 g/g or more than twice the value at baseline if the baseline value was >1 g/g; and 2) Impaired renal function: a reproducible decrease in eGFR of >20% accompanied by at least 1 of the following: proteinuria (>1 g/g), red blood cell casts, or white blood cell casts. f Renal-related treatment failure was prospectively defined as intake of prohibited medications for adjudicated inadequate lupus nephritis control or renal flare management. Percentage (Number) of subjects with event b 28% (63) 16% (35) Time to event c 0.5 (0.3, 0.8) P = 0.001 Components of endpoint d (percentage of subjects with event) End-stage renal disease (ESRD) 0.4% 1% Doubling of serum creatinine from baseline 4% 1% Renal worsening e 18% 8% Renal-related treatment failure f 16% 9% Death 1% 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. Figure 1 Figure 2 14.4 Intravenous Administration in Pediatric Subjects with Active SLE Trial 6: Active SLE - BENLYSTA 10 mg/kg in Pediatric Subjects - Intravenous The safety and efficacy of BENLYSTA was evaluated in an international, randomized, double‑blind, placebo‑controlled, 52‑week, pharmacokinetics (PK), efficacy and safety trial (Trial 6) conducted in 93 pediatric subjects with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Subjects had active SLE disease, defined as a SELENA-SLEDAI score ≥6 and positive autoantibodies at screening as defined in the adult trials. Subjects were on a 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: 6 to 17). The majority (95%) of subjects were female. More than 50% of subjects had 3 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 subjects 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 a numerically higher proportion of pediatric subjects achieving a response in SRI‑4 and its components in pediatric subjects receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy ( Table 9 ). Table 9. Response Rate at Week 52 a in Pediatric Subjects 5 Years of Age and Older with Active SLE (Intravenous Treatment) (Trial 6) a Based on a non-powered trial. b Analyses excluded any subject missing a baseline assessment for any of the components (1 for placebo). Response b Placebo + Standard Therapy (n = 39) BENLYSTA 10 mg/kg + Standard Therapy (n = 53) SLE Responder Index 44% 53% Odds Ratio (95% CI) vs. Placebo 1.49 (0.64, 3.46) Components of SLE Responder Index Percent of subjects with reduction in SELENA‑SLEDAI ≥4 44% 55% Percent of subjects with no worsening by BILAG index 62% 74% Percent of subjects with no worsening by PGA 67% 76% Other Endpoints SRI-6 using SELENA SLEDAI ≥6-point reduction 34% 41% Proportion of subjects with a sustained SRI response 41% 43% Effect on Concomitant Steroid Treatment: At baseline, 95% of pediatric subjects were receiving prednisone. Among those pediatric subjects, 20% of pediatric subjects 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 subjects on placebo plus standard therapy. Effect on Severe SLE Flares: In Trial 6, the probability of experiencing a 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 subjects reporting at least one severe flare during the trial was numerically lower in pediatric subjects receiving BENLYSTA plus standard therapy (17%) compared with those receiving placebo plus standard therapy (35%). Pediatric subjects receiving BENLYSTA 10 mg/kg plus standard therapy had a 64% lower risk of experiencing a severe flare during the 52 weeks of observation, relative to the placebo plus standard therapy group. Of the pediatric subjects experiencing a severe flare, the median time to the first severe flare was 150 days in pediatric subjects receiving BENLYSTA plus standard therapy compared with 113 days in pediatric subjects receiving placebo plus standard therapy. 14.5 Subcutaneous Administration in Adults with Active SLE Trial 7: Active SLE – BENLYSTA 200 mg - Subcutaneous The safety and effectiveness of BENLYSTA administered subcutaneously were evaluated in a randomized, double‑blind, placebo‑controlled trial involving 836 adult subjects with SLE according to the American College of Rheumatology criteria (Trial 7, NCT01484496). Subjects 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 subjects with active SLE disease. Subjects had to have a 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 subject characteristics were observed between treatment groups. In some countries, treatment with a B‑cell–targeted agent was permitted if received a year or more prior to baseline; otherwise, treatment with a B‑cell–targeted agent was not permitted. Subjects were excluded from the trial if they were currently receiving other biologic agents. Anti‑tumor necrosis factor therapy, intravenous cyclophosphamide, interleukin‑1 receptor antagonist, IVIG, prednisone >100 mg/day, and plasmapheresis were not permitted within the previous 3 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 subjects (approximately 80%) were receiving 2 or more classes of SLE medications. More than 50% of subjects had 3 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 subjects had some degree of renal activity and less than 15% of subjects had activity in the vascular, cardio‑respiratory, or CNS systems. Subjects 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 subjects 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 subjects achieving an SRI‑4 response was significantly higher in subjects 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 10 ). Table 10. Clinical Response Rate in Adult Subjects with Active SLE after 52 Weeks of Subcutaneous Treatment (Trial 7) a Analyses excluded any subject missing a baseline assessment for any of the components (1 for placebo; 2 for belimumab). b Subjects dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. A higher proportion of subjects receiving placebo plus standard therapy were considered as failures for this reason compared with the group receiving BENLYSTA plus standard therapy. Response a Placebo + Standard Therapy (n = 279) BENLYSTA + Standard Therapy (n = 554) SLE Responder Index-4 (SRI-4) b 48% 61% P = 0.0006 Odds Ratio (95% CI) vs. placebo 1.7 (1.3, 2.3) Components of SLE Responder Index-4 (SRI-4) Percent of subjects with reduction in SELENA-SLEDAI ≥4 49% 62% Percent of subjects with no worsening by BILAG index 74% 81% Percent of subjects with no worsening by PGA 73% 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 Visit a (Subcutaneous Treatment in Adult Subjects with Active SLE) (Trial 7) a The same subjects may not have responded at each timepoint. Effect in Black/African ‑ American Subjects: Exploratory sub‑group analyses of SRI‑4 response rate in Black subjects (n = 91) were performed. The SRI‑4 response rate in Black subjects 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 subjects were receiving prednisone at doses >7.5 mg/day. Among these subjects, 18% of subjects 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 subjects 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 a 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 subjects reporting at least 1 severe flare during the trial was lower in subjects treated with BENLYSTA plus standard therapy (11%) compared with those receiving placebo plus standard therapy (18%). Subjects treated with BENLYSTA plus standard therapy had a 49% lower risk of experiencing at least 1 severe flare during the 52 weeks of observation, relative to the subjects receiving placebo plus standard therapy (HR = 0.51 [95% CI: 0.35, 0.74]). Of the subjects experiencing a severe flare, the median time to the first severe flare was delayed in subjects receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy (171 days vs. 118 days). Figure 3

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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