BENLYSTA

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 reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight. 4. If a mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, do not exceed 500 rpm or swirl the vial for more 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 Ringer’s Injection, USP to a volume of 250 mL for intravenous infusion. To prepare the intravenous infusion solution for patients whose body weight is less than or equal to 40 kg, a 100 mL bag or bottle of normal saline, half-normal saline, or Lactated Ringer’s Injection may be used such that the resulting belimumab concentration in the infusion bag does not exceed 4 mg/mL. From a 250‑mL (or 100‑mL) infusion bag or bottle of normal saline, half-normal saline, or Lactated Ringer’s Injection, withdraw and discard a volume equal to the volume of the reconstituted solution of BENLYSTA required for the patient’s dose. Then add the required volume of the reconstituted solution of BENLYSTA into the intravenous infusion solution in the infusion bag or bottle. Gently invert the bag or bottle to mix the intravenous infusion solution. Any unused solution in the vials must be discarded. 2. Visually inspect parenteral drug products 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. If the reconstituted solution of BENLYSTA is not used immediately, store, protect from direct sunlight and refrigerate at 36°F to 46°F (2°C to 8°C). Store solutions of BENLYSTA diluted in normal saline, half‑normal saline, or Lactated Ringer’s Injection at 36°F to 46°F (2°C to 8°C) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed 8 hours. 4. No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed. 2.3 Recommended Subcutaneous Dosage, and Preparation and Administration Instructions The recommended subcutaneous BENLYSTA dosage in patients 5 years of age and older with active SLE or lupus nephritis is provided in Table 1 . Administer BENLYSTA subcutaneously in the abdomen or thigh. For patients less than 10 years of age, BENLYSTA must be administered by a healthcare professional or trained caregiver. Table 1. Recommended Subcutaneous Dosage of BENLYSTA a The prefilled syringe has not been studied in pediatric patients 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 • Patients greater than or equal to 40 kg: 200 mg once weekly • Patients 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 • Patients greater than or equal to 40 kg: 400 mg b once weekly for 4 doses, followed by 200 mg once weekly • Patients 15 kg to less than 40 kg: 200 mg once weekly for 4 doses, followed by 200 mg once every 2 weeks Administration Instructions for Subcutaneous Injection 1. Administer the first subcutaneous injection of BENLYSTA under the supervision of a healthcare provider. Provide patients or caregivers with proper training on subcutaneous administration and education about signs and symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.2 )] . For adults and pediatric patients 10 years of age and older, subsequent subcutaneous BENLYSTA administrations may be performed by the patient or trained caregiver, if determined to be appropriate. For pediatric patients less than 10 years of age, subsequent subcutaneous BENLYSTA administrations must be performed by a healthcare provider or trained caregiver. 2. Instruct the patient or caregiver to follow the directions for administration provided in the Instructions for Use. 3. Instruct the patient or caregiver 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 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 or caregiver not to use the BENLYSTA autoinjector or prefilled syringe if dropped on a hard surface. 5. When injecting in the same body region, advise the patient or caregiver to use a different injection site for each injection; never give injections into areas where the skin is tender, bruised, red, or hard. When administering a 400‑mg dose, inject each 200‑mg injection at least 5 cm (approximately 2 inches) apart. 6. Instruct the patient or caregiver to administer BENLYSTA, preferably on the same day each week or the same day of alternate weeks, as appropriate. 7. If a dose is missed, instruct the patient or caregiver to administer a dose as soon as the patient remembers. Thereafter, the patient can resume dosing on their usual day of administration or start a new schedule from the day that the missed dose was administered. 2.4 Switching from Intravenous to Subcutaneous BENLYSTA Use Active SLE Administer the first subcutaneous BENLYSTA dose 1 to 4 weeks after the last intravenous dose. To switch: • Adults and pediatric patients greater than or equal to 40 kg, administer the first 200 mg subcutaneous dose 1 to 4 weeks after the last intravenous dose, then continue 200 mg subcutaneous dosing once weekly. • Pediatric patients 15 kg to less than 40 kg, administer the first 200 mg subcutaneous dose 1 to 4 weeks after the last intravenous dose, then continue 200 mg subcutaneous dosing every 2 weeks. Active Lupus Nephritis Patients may be switched from intravenous BENLYSTA treatment to subcutaneous BENLYSTA treatment after completing at least 2 intravenous doses. To switch: • Adults and pediatric patients greater than or equal to 40 kg, administer the first 200 mg subcutaneous dose 1 to 2 weeks after the last intravenous dose, then continue 200 mg subcutaneous dosing once weekly. • Pediatric patients 15 kg to less than 40 kg, administer the first 200 mg subcutaneous dose 1 to 2 weeks after the last intravenous dose, then continue 200 mg subcutaneous dosing every 2 weeks.

4 CONTRAINDICATIONS BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab. Previous anaphylaxis to belimumab. ( 4 )

5 WARNINGS AND PRECAUTIONS • 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 )] .

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 )] .

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 )] • 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 )].

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 ( 5.5 )] . 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 the MRHD of 200 mg subcutaneously (on an area under the curve [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 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.