Belimumab

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 )

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 educa

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 )] .

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

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 )] .

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 receivin

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.