Belimumab

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.

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 )].

12.3 Pharmacokinetics Intravenous Infusion in Adults Systemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table 3 are based on population parameter estimates from 563 adult subjects with active SLE who received BENLYSTA 10 mg/kg . Table 3. Population Pharmacokinetic Parameters in Adult Subjects with Active SLE after Intravenous Infusion of BENLYSTA 10 mg/kg a a Intravenous infusions were administered at 2‑week intervals for the first 3 doses and at 4‑week intervals thereafter. Pharmacokinetic Parameter Population Estimates (n = 563) Peak concentration at steady state (C max,ss , mcg/mL) 313 Area under the curve (AUC 0-∞ , day•mcg/mL) 3,083 Distribution half-life (t ½ , days) 1.8 Terminal half-life (t ½ , days) 19.4 Systemic clearance (CL, mL/day) 215 Volume of distribution at steady state (Vss, L) 5 Lupus Nephritis: A population pharmacokinetic analysis was conducted in 224 adult subjects with active lupus nephritis who received belimumab 10 mg/kg intravenously (Days 0, 14, 28, and then every 28 days up to 104 weeks) plus standard therapy in Trial 5 [see Clinical Studies ( 14.3 )] . In these subjects, due to additional clearance associated with proteinuria, belimumab exposure was initially lower than observed in SLE studies and lower belimumab exposure was observed in subjects with higher proteinuria. When the proteinuria was decreased to approximately ≤1 g/g after treatment, belimumab clearance and exposure were similar to that observed in subjects with active SLE who received belimumab 10 mg/kg intravenously. The available data do not support a dose adjustment in patients with high proteinuria. Subcutaneous Injection in Adults Systemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table 4 are based on population parameter estimates from 661 adult subjects with active SLE after subcutaneous administration of belimumab 200 mg once weekly. The time to reach maximum serum concentration (C max ) was 2.6 days (T max ) after administration at steady state. The bioavailability of belimumab was approximately 74%. With weekly subcutaneous administration there were minor fluctuations around the steady‑state average concentration (C avg,ss 104 mcg/mL), with the steady‑state trough concentration (C min,ss ) (97 mcg/mL) being only slightly below C avg,ss . Table 4. Population Pharmacokinetic Parameters in Adults with Active SLE after Subcutaneous Administration of BENLYSTA 200 mg Once Weekly Pharmacokinetic Parameter Population Estimates (n = 661) Peak concentration at steady state (C max,ss , mcg/mL) 108 Area under the curve (AUC 0-∞ , day•mcg/mL) 726 Distribution half-life (t ½ , days) 1.1 Terminal half-life (t ½ , days) 18.3 Systemic clearance (CL, mL/day) 204 Volume of distribution at steady state (Vss, L) 5 Lupus Nephritis: Based on population pharmacokinetic modeling and simulation of the subcutaneous 400-mg weekly loading dose, the average belimumab concentration during the first 12 weeks was predicted to be 78 mcg/mL, which is similar to the estimated concentration of 89 mcg/mL for intravenous administration. The loading dose of 400 mg weekly provides steady-state concentrations from Week 2 of dosing. The steady-state average concentrations of subcutaneous administration of belimumab 200 mg once weekly in adults with active lupus nephritis are predicted to be similar to those observed in adults with active lupus nephritis receiving belimumab 10 mg/kg intravenously every 4 weeks. Specific Populations The following information is based on the population pharmacokinetic analyses of intravenous administration and subcutaneous administration of BENLYSTA. Age: Age did not significantly influence the pharmacokinetics of belimumab, where the majority of subjects were between 18 and 45 years of age (70% with intravenous dosing; 74% with subcutaneous dosing). Geriatric Patients : Limited pharmacokinetic data are available for elderly patients as less than 2% of the subjects included in the pharmacokinetic analysis were 65 years of age or older [see Use in Specific Populations ( 8.5 )] . Pediatric Patients : • Intravenous Administration in Pediatric Patients with Active SLE: The pharmacokinetic parameters of belimumab after intravenous administration in pediatric subjects with active SLE are based on individual parameter estimates from a population pharmacokinetic analysis of 53 pediatric subjects with active SLE (Trial 6). Following intravenous administration of 10 mg/kg on Days 0, 14, and 28, and at 4‑week intervals thereafter, belimumab exposures were similar between pediatric and adult subjects with active SLE. Steady‑state geometric mean C max , C min , C avg , and AUC values were 305, 42, 92 mcg/mL, and 2,569 day•mcg/mL in the 5‑year to 11‑year‑old group, and 317, 52, 112 mcg/mL and 3,126 day•mcg/mL in the 12‑year to 17‑year‑old group [see Use in Specific Populations ( 8.4 )] . • Subcutaneous Administration in Pediatric Patients with Active SLE: The pharmacokinetic parameters of belimumab, following subcutaneous administration in pediatric subjects with active SLE, are based on a population pharmacokinetic analysis derived from 25 pediatric subjects with active SLE who received BENLYSTA subcutaneously and Trial 6 (a Phase 2 trial in pediatric subjects with active SLE receiving BENLYSTA intravenously). Following subcutaneous administration of 200 mg of BENLYSTA in pediatric subjects 5 years to less than 18 years of age, either weekly (subjects weighing greater than or equal to 40 kg) or every 2 weeks (subjects weighing 15 to less than 40 kg), the steady state average belimumab concentration is estimated to be similar to that of adult subjects with active SLE following subcutaneous administration of BENLYSTA 200 mg weekly and similar to that of pediatric subjects with active SLE following intravenous administration of 10 mg/kg BENLYSTA on Days 0, 14, and 28, and at 4‑week intervals thereafter. Simulated steady‑state geometric mean C max and AUC are estimated to be 110 mcg/mL and 1,328 day•mcg/mL for pediatric subjects (weighing 15 to less than 40 kg) receiving BENLYSTA 200 mg every 2 weeks, and 134 mcg/mL and 899 day•mcg/mL for pediatric subjects (weighing greater than or equal to 40 kg) receiving BENLYSTA 200 mg once weekly [see Use in Specific Populations ( 8.4 )] . • Intravenous Administration in Pediatric Patients with Active Lupus Nephritis: The pharmacokinetics of belimumab, following intravenous administration in pediatric patients with active lupus nephritis, were estimated based on a population pharmacokinetic model developed from intravenous pharmacokinetics data from 224 adults with active lupus nephritis in Trial 5 and validated using intravenous pharmacokinetics data from 53 pediatric subjects with active SLE in Trial 6. Based on modeling and simulation results, with intravenous administration of 10 mg/kg on Days 0, 14, and 28 and at 4‑week intervals thereafter, the simulated belimumab exposures for both the 5‑year to 11‑year‑old group and the 12‑year to 17‑year‑old group of pediatric subjects were estimated to be comparable to adults with active lupus nephritis [see Use in Specific Populations ( 8.4 )] . • Subcutaneous Administration in Pediatric Patients with Active Lupus Nephritis: The pharmacokinetics of belimumab, following subcutaneous administration in pediatric patients with active lupus nephritis, were extrapolated from previously developed pediatric and adult pharmacokinetic models (Trials 5 and 6) and validated using data from pediatric subjects with active SLE who received BENLYSTA intravenously (Trial 6) and subcutaneously. Based on the modeling and simulation results, following subcutaneous administration of BENLYSTA in pediatric subjects with active lupus nephritis aged 5 years to less than 18 years, receiving either 400 mg once weekly for 4 doses, then 200 mg every week thereafter (subjects weighing greater than or equal to 40 kg) or 200 mg once weekly for 4 doses then 200 mg once every 2 weeks (subjects weighing 15 to less than 40 kg), the simulated belimumab exposures were estimated to be comparable to that of adults with active lupus nephritis [see Use in Specific Populations ( 8.4 )] . Male and Female Patients: Gender did not significantly influence belimumab pharmacokinetics in the largely female trial population (94% with intravenous dosing; 85% with subcutaneous dosing). Racial Groups: Race did not significantly influence belimumab pharmacokinetics. The racial distribution with intravenous administration was 53% White, 16% Asian, 16% Alaska native/American Indian, and 14% Black in Trials 1, 2, and 3. Trial 4 enrolled only Black subjects. The racial distribution with subcutaneous administration (Trial 7) was 61% White, 20% Asian, 11% Black, and 6% Alaska native/American Indian. Weight: Body weight and body mass index (BMI) had no clinically relevant effect on the pharmacokinetics of belimumab administered subcutaneously in adults. No dose adjustment is recommended in adults based on weight or BMI for subcutaneous administration. The effects of body weight on belimumab exposure, after subcutaneous administration in pediatric patients, have been determined using a population pharmacokinetic model. Pediatric patients with lower body weight have lower belimumab clearance and volume of distribution. To ensure belimumab exposures remain within acceptable limits and are consistent across the pediatric weight range, patients with lower body weight are given a lower dose of BENLYSTA or administered BENLYSTA less frequently [see Dosage and Administration ( 2.3 )] . Patients with Renal Impairment: No formal trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. BENLYSTA was studied in a limited number of adult subjects with SLE who had mild (CrCl ≥60 and <90 mL/min), moderate (CrCl ≥30 and <60 mL/min), or severe (CrCl ≥15 and <30 mL/min) renal impairment: 770 subjects with mild renal impairment, 261 subjects with moderate renal impairment, and 14 subjects with severe renal impairment received belimumab intravenously; 121 subjects with mild renal impairment and 30 subjects with moderate renal impairment received belimumab subcutaneously [see Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment: No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels did not significantly influence belimumab pharmacokinetics [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies No formal drug interaction studies have been conducted with BENLYSTA. Concomitant use of mycophenolate, cyclophosphamide, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and/or HMG‑CoA reductase inhibitors did not significantly influence belimumab pharmacokinetics. Coadministration of steroids and angiotensin‑converting enzyme (ACE) inhibitors resulted in an increase of systemic clearance of belimumab that was not clinically significant because the magnitude was well within the range of normal variability of clearance. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated.