BENLYSTA

Contraindications ( 4 ) 8/2026 Warnings and Precautions, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis ( 5.3 ) 8/2026

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION • See Full Prescribing Information for complete preparation and administration information. ( 2.1 , 2.2 , 2.3 ) • Intravenous dosage for active SLE or lupus nephritis: o 10 mg/kg at 2‐week intervals for the first 3 doses and at 4‐week intervals thereafter. o Reconstitute, dilute, and administer as an intravenous infusion over a period of 1 hour. ( 2.2 ) o Consider prophylactic premedication for infusion reactions and hypersensitivity reactions. ( 2.1 , 2.2 ) • Subcutaneous dosage for active SLE or lupus nephritis: ( 2.3 ) 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. Indication Adults (Autoinjector or Prefilled Syringe) Pediatric Patients 5 Years of Age and Older (Weight ‐ Based Dosing) (Autoinjector Only) a Active SLE 200 mg once weekly • ≥40 kg: 200 mg once weekly • 15 kg to less than 40 kg: 200 mg once every 2 weeks Active Lupus Nephritis 400 mg b once weekly for 4 doses, followed by 200 mg once weekly • ≥40 kg: 400 mg b once weekly for 4 doses, followed by 200 mg once weekly • 15 kg to less than 40 kg: 200 mg once weekly for 4 doses, followed by 200 mg once every 2 weeks 2.1 Important Administration Instructions BENLYSTA may be administered intravenously or subcutaneously [see Dosage and Administration ( 2.2 , 2.3 )]. 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). Precautions Prior to Intravenous Use BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis [see Warnings and Precautions ( 5.2 )]. Prior to intravenous dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 )] . 2.2 Recommended Intravenous Dosage, and Preparation and Administration Instructions BENLYSTA for intravenous use must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus. Recommended Dosage and Administration The recommended intravenous BENLYSTA dosage in patients 5 years of age and older with active SLE or lupus nephritis is 10 mg/kg at 2‐week intervals for the first 3 doses and at 4‐week intervals thereafter. Reconstitute, dilute, and administer as an intravenous infusion over a period of 1 hour. Do not concomitantly infuse BENLYSTA 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. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion must be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . Preparation of the Intravenous Solution BENLYSTA for intravenous use is provided as a lyophilized powder in a single‐dose vial and should be reconstituted and diluted by a healthcare professional using aseptic technique as follows. Use of a 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 a concentration of 80 mg/mL belimumab. • Reconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP. • Reconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP. 3. Direct the stream of sterile water towards the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature during re …

3 DOSAGE FORMS AND STRENGTHS Intravenous Infusion For injection: 120 mg or 400 mg of belimumab as a lyophilized powder in single‐dose vials for reconstitution and dilution prior to intravenous infusion. Subcutaneous Injection Injection: 200 mg/mL of belimumab as a clear to opalescent and colorless to pale yellow solution in a single-dose prefilled autoinjector or a single-dose prefilled glass syringe. • Intravenous Infusion (for injection): 120 mg or 400 mg of belimumab lyophilized powder in single‐dose vial for reconstitution and dilution prior to intravenous infusion. ( 3 ) • Subcutaneous Injection (injection): 200 mg/mL of belimumab in single‐dose prefilled autoinjector or single‐dose prefilled syringe. ( 3 )

4 CONTRAINDICATIONS BENLYSTA is contraindicated in patients with a prior history of: • Anaphylaxis with belimumab [see Warnings and Precautions ( 5.2 )]. • Stevens-Johnson syndrome or toxic epidermal necrolysis with belimumab [see Warnings and Precautions ( 5.3 )]. Previous anaphylaxis, Stevens‐Johnson syndrome, or toxic epidermal necrolysis as a reaction to belimumab. ( 4 )

6 ADVERSE REACTIONS 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 )] • Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see Warnings and Precautions ( 5.3 )] • Depression and Suicidality [see Warnings and Precautions ( 5.4 )] • Malignancy [see Warnings and Precautions ( 5.5 )] 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 …

7 DRUG INTERACTIONS 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 [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS 8.1 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 [see Clinical Pharmacology ( 12.1 )] . 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 [see Warnings and Precautions ( 5.6 )] . 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 [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 9 times the MRHD of 10 mg/kg intravenously or 20 times t …

12.1 Mechanism of Action BENLYSTA is a BLyS-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. BENLYSTA does not bind B cells directly, but by binding BLyS, BENLYSTA inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

11 DESCRIPTION Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a murine cell (NS0) expression system. Intravenous Infusion BENLYSTA (belimumab) for injection is a sterile, white to off-white, preservative‐free, lyophilized powder in a single-dose vial for reconstitution and dilution prior to intravenous infusion. BENLYSTA for injection is supplied as 120 mg per vial and 400 mg per vial and requires reconstitution with Sterile Water for Injection, USP (1.5 mL and 4.8 mL, respectively) to obtain a concentration of 80 mg/mL [see Dosage and Administration ( 2.2 )] . After reconstitution, each vial allows for withdrawal of 1.5 mL (120 mg) or 5 mL (400 mg). Each mL delivers 80 mg belimumab, citric acid (0.16 mg), polysorbate 80 (0.4 mg), sodium citrate (2.7 mg), and sucrose (80 mg), with a pH of 6.5. The vial stoppers are not made with natural rubber latex. Subcutaneous Injection BENLYSTA (belimumab) injection is a sterile, preservative-free, clear to opalescent, and colorless to pale yellow solution for subcutaneous use. It is supplied in a 1-mL single-dose prefilled autoinjector with a fixed 27-gauge, half-inch needle or in a 1-mL single-dose prefilled syringe with a fixed 27-gauge, half-inch needle with a needle guard. Each 1 mL delivers 200 mg belimumab, L-arginine hydrochloride (5.3 mg), L-histidine (0.65 mg), L-histidine monohydrochloride (1.2 mg), polysorbate 80 (0.1 mg), and sodium chloride (6.7 mg), with a pH of 6.0. The autoinjectors and prefilled syringes are not made with natural rubber latex.

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Intravenous Infusion BENLYSTA (belimumab) for injection is a sterile, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous infusion provided in single‐dose glass vials with a rubber stopper (not made with natural rubber latex) and a flip‐off seal. Each 5‐mL vial contains 120 mg of belimumab. Each 20‐mL vial contains 400 mg of belimumab. BENLYSTA vials are supplied as follows: 120 mg belimumab in a 5‐mL single-dose vial (NDC 49401-101-01) 400 mg belimumab in a 20‐mL single-dose vial (NDC 49401-102-01) Refrigerate vials at 36°F to 46°F (2°C to 8°C). Store vials in the original carton until use to protect from light. Do not freeze. Avoid exposure to heat. 16.2 Subcutaneous Injection BENLYSTA (belimumab) injection is a clear to opalescent, and colorless to pale yellow solution for subcutaneous use. Each single-dose prefilled autoinjector or single-dose prefilled syringe is designed to deliver 200 mg of belimumab in 1 mL of solution and is supplied as follows: 200 mg/mL single-dose prefilled autoinjector with 27-gauge, half-inch needle attached (NDC 49401-088-01) in a carton of 4 (NDC 49401-088-35). 200 mg/mL single-dose prefilled glass syringe with 27-gauge, half-inch needle attached (NDC 49401-088-42) in a carton of 4 (NDC 49401-088-47). Prior to Dispensing Refrigerate prefilled autoinjectors and prefilled syringes at 36°F to 46°F (2°C to 8°C). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Avoid exposure to heat. Following Dispensing Refrigerate prefilled autoinjectors and prefilled syringes at 36°F to 46°F (2°C to 8°C). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Avoid exposure to heat. BENLYSTA may be stored outside of the refrigerator up to 86°F (30°C) for up to 12 hours if protected from sunlight. Do not use and do not place back in refrigerator if left out for more than 12 hours.