2.1 Important Administration Information

BENLYSTA may be administered as an intravenous infusion in patients aged 5 years and older or as a subcutaneous injection in patients aged 18 years and older. 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).

2.2 Recommended Intravenous Dosage for Adult and Pediatric Patients with SLE or Lupus Nephritis

Dosage

BENLYSTA for intravenous use must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus.

The recommended intravenous dosage 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. 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)].

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)].

Preparation of Intravenous Solutions

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.

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Reconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.

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Reconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.

3.

The stream of sterile water should be directed toward 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, it should not exceed 500 rpm and the vial swirled for no longer 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.

Parenteral drug products should be inspected visually 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.

The reconstituted solution of BENLYSTA, if not used immediately, should be stored protected from direct sunlight and refrigerated at 36°F to 46°F (2°C to 8°C). Solutions of BENLYSTA diluted in normal saline, half-normal saline, or Lactated Ringer’s Injection may be stored 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.

Administration Instructions for Intravenous Use

1.

The diluted solution of BENLYSTA should be administered by intravenous infusion over a period of 1 hour.

2.

BENLYSTA should not be infused concomitantly 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.

2.3 Recommended Subcutaneous Dosage for Adult Patients with SLE or Lupus Nephritis

Subcutaneous dosing of BENLYSTA has not been evaluated and is not approved for patients younger than 18 years of age.

Adult Patients with SLE

The recommended dosage is 200 mg once weekly given as a subcutaneous injection in the abdomen or thigh. Subcutaneous dosing is not based on weight.

If transitioning from intravenous therapy with BENLYSTA to subcutaneous administration, administer the first subcutaneous dose 1 to 4 weeks after the last intravenous dose.

Adult Patients with Lupus Nephritis

In patients initiating therapy with BENLYSTA for active lupus nephritis [see Clinical Studies (14.2)], the recommended dosage is a 400-mg dose (two 200-mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter. The dose is given via subcutaneous injection in the abdomen or thigh. The 400-mg dose for active lupus nephritis requires administration of 2 autoinjectors or 2 prefilled syringes as described below.

A patient with lupus nephritis may transition from intravenous therapy with BENLYSTA to subcutaneous therapy any time after the patient completes the first 2 intravenous doses. If transitioning, administer the first subcutaneous dose of 200 mg 1 to 2 weeks after the last intravenous dose.

Administration Instructions for Subcutaneous Injection

1.

It is recommended that the first subcutaneous injection of BENLYSTA should be under the supervision of a healthcare professional. The healthcare provider should provide proper training in subcutaneous technique and education about signs and symptoms of hypersensitivity reactions [see Warning and Precautions (5.2)]. A patient may self-inject or the patient caregiver may administer BENLYSTA subcutaneously after the healthcare provider determines it is appropriate.

2.

Instruct the patient or patient caregiver to follow the directions for administration provided in the Instructions for Use.

3.

Instruct the patient 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 patient 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 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 to use a different injection site for each injection; never give injections into areas where the skin is tender, bruised, red, or hard. When a 400-mg dose is administered at the same site, it is recommended that the 2 individual 200-mg injections be administered at least 5 cm (approximately 2 inches) apart.

6.

Instruct the patient to administer BENLYSTA 200 mg once a week, preferably on the same day each week.

7.

If a dose is missed, instruct the patient 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 weekly schedule from the day that the missed dose was administered.

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 patients receiving BENLYSTA compared with placebo, whereas fatal infections occurred more frequently in patients 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 confirmed PML, discontinue immunosuppressant therapy, including BENLYSTA.

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 patients (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 (2.2)].

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 patients 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 patients receiving BENLYSTA concomitantly with rituximab compared to patients 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)].

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.

Clinical Trials with Intravenous Administration in Adult and Pediatric Patients

Adult Patients with SLE: The data described in Table 1 reflect exposure to BENLYSTA administered intravenously plus standard therapy compared with placebo plus standard therapy in 2,133 adult patients with SLE in 3 controlled trials (Trials 1, 2, and 3). Patients 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 (14.1)]. 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 these trials, 93% of patients 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 patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA plus standard therapy and 7.1% for patients receiving placebo plus standard therapy. The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients 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 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with 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).

Infections: In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, the overall incidence of infections was 71% in patients receiving BENLYSTA compared with 67% in patients receiving placebo. The most frequent infections (>5% of patients 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 patients receiving BENLYSTA and 1.0% of patients receiving placebo.

In a randomized, double-blind, placebo-controlled, 104-week trial of active lupus nephritis in adults receiving BENLYSTA administered intravenously (N = 448), the overall incidence of infections was 82% in patients receiving BENLYSTA compared with 76% in patients receiving placebo.

Serious Infections: In controlled trials of BENLYSTA administered intravenously in adults with SLE, the incidence of serious infections was 6.0% in patients receiving BENLYSTA and 5.2% in patients 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 patients receiving BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

In a randomized, double-blind, placebo-controlled, 104-week trial of active lupus nephritis in adults receiving BENLYSTA administered intravenously, serious infections occurred in 14% of patients receiving BENLYSTA and in 17% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving BENLYSTA and in 0.9% (2/224) of patients receiving placebo.

In a randomized, double-blind, placebo-controlled, 52-week, postmarketing safety trial of BENLYSTA administered intravenously in adults with SLE (N = 4,003), the incidence of serious infections was 3.7% in patients receiving BENLYSTA compared with 4.1% in patients receiving placebo. Serious infections leading to discontinuation of treatment occurred in 1.0% of patients receiving BENLYSTA and in 0.9% of patients receiving placebo. Fatal infections occurred in 0.45% (9/2,002) of patients receiving BENLYSTA and in 0.15% (3/2,001) of patients receiving placebo, where the incidence of all-cause mortality was 0.50% (10/2,002) in patients receiving BENLYSTA and 0.40% (8/2,001) in patients receiving placebo.

Hypersensitivity Reactions, including Anaphylaxis: In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea.

Infusion-Related Reactions: In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions.

Depression and Suicidality: In controlled clinical trials of BENLYSTA administered intravenously in adults with SLE (N = 2,133), 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 patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.4% (6/1,458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg).

In a randomized, double-blind, placebo-controlled, 52-week, postmarketing safety trial of BENLYSTA administered intravenously in adults with SLE (N = 4,003), serious psychiatric events were reported in 1% (20/2,002) of patients receiving BENLYSTA and 0.3% (6/2,001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2,002) of patients 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 patients receiving BENLYSTA and 0.2% (5/2,001) of patients receiving placebo. On the Columbia-Suicide Severity Rating Scale (C-SSRS), 2.4% (48/1,974) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 2% (39/1,988) of patients receiving placebo. No suicide was reported in either group.

The intravenous trials above did not exclude patients with a history of psychiatric disorders.

Malignancy: In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients 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 patients receiving BENLYSTA and placebo, respectively.

Black/African-American Patients: The safety of BENLYSTA 10 mg/kg administered intravenously plus standard therapy (n = 331) compared with placebo plus standard therapy (n = 165) in Black patients with SLE (Trial 4) was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in the overall population [see Clinical Studies (14.1)].

Adult Patients with 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 (14.2)]. The adverse reactions observed were consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in patients with 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.

Pediatric Patients: The safety of BENLYSTA administered intravenously plus standard therapy (n = 53) compared with placebo plus standard therapy (n = 40) was evaluated in 93 pediatric patients with SLE (Trial 6). The adverse reactions observed were consistent with those observed in adults with SLE [see Clinical Studies (14.3)].

Clinical Trials with Subcutaneous Administration in Adults

The data described below reflect exposure to BENLYSTA administered subcutaneously plus standard therapy compared with placebo plus standard therapy in 836 patients with SLE in a controlled trial (Trial 7). In addition to standard therapy, patients received BENLYSTA 200 mg (n = 556) or placebo (n = 280) (2:1 randomization) once weekly for up to 52 weeks [see Clinical Studies (14.4)].

In the trial, 81% of patients treated with BENLYSTA plus standard therapy reported an adverse event compared with 84% treated with placebo plus standard therapy. The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trial was 7.2% of patients receiving BENLYSTA plus standard therapy and 8.9% of patients 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 a controlled trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), the overall incidence of infections was 55% in patients receiving BENLYSTA compared with 57% in patients receiving placebo. The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously.

Serious Infections: In a controlled trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), the incidence of serious infections was 4.1% in patients receiving BENLYSTA and 5.4% in patients receiving placebo. Fatal infections occurred in 0.5% (3/556) of patients receiving BENLYSTA and in none of the patients receiving placebo (0/280).

Depression and Suicidality: In a controlled trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), which excluded patients with a history of psychiatric disorders, psychiatric events were reported in 6% of patients receiving BENLYSTA and 11% of patients receiving placebo. Depression-related events were reported in 2.7% (15/556) of patients receiving BENLYSTA and 3.6% (10/280) of patients receiving placebo. Serious psychiatric events were reported in 0.2% (1/556) of patients receiving BENLYSTA and in no patients receiving placebo. There were no serious depression-related events or suicides reported in either group. On the C‑SSRS, 1.3% (7/554) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 0.7% (2/277) of patients receiving placebo.

Malignancy: In a controlled clinical trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), the reports of malignancies were similar to those reported with BENLYSTA administered intravenously.

Injection Site Reactions: In a controlled clinical trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), the frequency of injection site reactions was 6.1% (34/556) for patients receiving BENLYSTA plus standard therapy and 2.5% (7/280) for patients 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 Rituximab in Adults: BENLYSTA administered subcutaneously in combination with rituximab was studied in a Phase III, randomized, double-blind, placebo-controlled, 104-week study in adult patients with SLE. Patients 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%), serious infections (2.8%, 5.3%, 9.0%), and post-injection systemic reactions (9.7%, 5.3%, 13.2%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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.

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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 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. 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.

8.2 Lactation

Risk Summary

No information is available on the presence of belimumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Belimumab was detected in the milk of cynomolgus monkeys; however, due to species-specific differences in lactation physiology, animal data may not predict drug levels in human milk. Maternal IgG is known to be present in human milk. If belimumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to belimumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of BENLYSTA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BENLYSTA, and any potential adverse effects on the breastfed child from BENLYSTA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Following an assessment of benefit versus risk, if prevention of pregnancy is warranted, females of reproductive potential should use effective contraception during treatment and for at least 4 months after the final treatment.

8.4 Pediatric Use

Safety and effectiveness of BENLYSTA have been established for the treatment of SLE and lupus nephritis in pediatric patients 5 to 17 years old.

Use of BENLYSTA in pediatric patients with SLE is supported by evidence from pharmacokinetic (PK) and efficacy results from a pediatric study (Trial 6), as well as PK exposure and extrapolation of the established efficacy of BENYLSTA plus standard therapy from the Phase 3 intravenous studies in adults with SLE. A randomized, double‑blind, placebo‑controlled, PK, efficacy, and safety study (Trial 6) to evaluate intravenously administered BENLYSTA 10 mg/kg plus standard therapy compared with placebo plus standard therapy over 52 weeks was conducted in 93 pediatric patients with SLE. The proportion of pediatric patients achieving an SRI-4 response was higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. Pediatric patients receiving BENLYSTA plus standard therapy also had a lower risk of experiencing a severe flare compared with placebo plus standard therapy [see Clinical Studies (14.3)]. Pharmacokinetics were evaluated in a total of 53 pediatric patients with SLE and were consistent with the adult population with SLE [see Clinical Pharmacology (12.3)].

Use of BENLYSTA in pediatric patients with active lupus nephritis is based on the extrapolation of efficacy from the intravenous study in adults (n = 224) with active lupus nephritis, and supported by pharmacokinetic data from intravenous studies in adults (n = 224) with active lupus nephritis and from pediatric patients (n = 53) with SLE. Estimated belimumab exposures for pediatric patients were comparable to adults with active lupus nephritis [see Clinical Pharmacology (12.3)].

The safety and effectiveness of intravenous administration of BENLYSTA have not been established in pediatric patients younger than 5 years of age.

The safety and effectiveness of subcutaneous administration of BENLYSTA have not been established in pediatric patients younger than 18 years of age.

8.5 Geriatric Use

Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects. Use with caution in geriatric patients.

8.6 Renal Impairment

The safety and efficacy of BENLYSTA were evaluated in studies that included patients with SLE who had mild (creatinine clearance [CrCl] ≥60 and <90 mL/min), moderate (CrCl ≥30 and <60 mL/min), or severe (CrCl ≥15 and <30 mL/min) renal impairment. No dosage adjustment is recommended in patients with renal impairment.

8.7 Hepatic Impairment

No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. No dosage adjustment is recommended in patients with hepatic impairment.

8.8 Racial Groups

In Trial 2 and Trial 3 (intravenous dosing), SLE Responder Index-4 (SRI-4) response rates were lower for Black patients receiving BENLYSTA plus standard therapy relative to Black patients receiving placebo plus standard therapy [see Clinical Studies (14.1)].

In Trial 4 (intravenous dosing), a 2:1 randomized, placebo-controlled trial in Black patients, SLE Responder Index (SRI-S2K) response rates were higher for Black patients receiving BENLYSTA plus standard therapy (49%) relative to Black patients receiving placebo plus standard therapy (42%). However, the treatment difference was not statistically significant [see Clinical Studies (14.1)].

In Trial 7 (subcutaneous dosing), SRI-4 response was 45% (26/58) in Black patients receiving BENLYSTA plus standard therapy compared with 39% (13/33) in Black patients receiving placebo plus standard therapy [see Clinical Studies (14.4)].

The safety profile of BENLYSTA in Black patients was consistent with the known safety profile of BENLYSTA administered in the overall population [see Adverse Reactions (6.1)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Treatment with BENLYSTA in adult patients significantly reduced circulating CD19+, CD20+, naïve, and activated B cells, and the SLE B‑cell subset at Week 52. Reductions in naïve and the SLE B‑cell subset were observed as early as Week 8 and sustained to Week 52. Memory cells increased initially and slowly declined toward baseline levels by Week 52.

Treatment with BENLYSTA in adult patients led to reductions in IgG and anti-double-stranded DNA antibodies (anti-dsDNA) which were observed as early as Week 8 and sustained through Week 52. In patients with low complement levels at baseline, treatment led to increases in complement C3 and C4 as early as Week 12 and were sustained through Week 52.

The pharmacodynamic response observed in Black patients (Trial 4) was consistent with the previous studies.

In patients with active lupus nephritis (Trial 5), following treatment with BENLYSTA, there was a decrease in serum IgG as early as Week 4, and subsequently there was an increase in serum IgG levels which was associated with decreased proteinuria. Reductions in autoantibodies, increases in complement, and reductions in circulating total B cells and B‑cell subsets observed were consistent with the SLE studies.

In Trial 6 (pediatric dosing), the pharmacodynamic response was consistent with the adult data.

The clinical relevance of above mentioned pharmacodynamic biomarkers has not been established.

12.3 Pharmacokinetics

Intravenous Infusion in Adults

Systemic Lupus Erythematosus: The pharmacokinetic parameters displayed in Table 2 are based on population parameter estimates from 563 adult patients who received BENLYSTA 10 mg/kg.

Lupus Nephritis: A population pharmacokinetic analysis was conducted in 224 adult patients with 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 [see Clinical Studies (14.2)]. In patients with lupus nephritis, due to additional clearance associated with proteinuria, belimumab exposure was initially lower than observed in SLE studies and lower belimumab exposure was observed in patients 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 patients with 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 3 are based on population parameter estimates from 661 subjects after subcutaneous administration of belimumab 200 mg once weekly. The time to reach maximum serum concentration (Cmax) was 2.6 days (Tmax) after administration at steady state. The bioavailability of belimumab was approximately 74%. With weekly subcutaneous administration there were minor fluctuations around the average concentration (Cavg 104 mcg/mL), with Cmin (97 mcg/mL) being only slightly below Cavg.

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 lupus nephritis are predicted to be similar to those observed in adults with 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 (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 or older [see Use in Specific Populations (8.5)].

Pediatric Patients: The pharmacokinetic parameters of belimumab are based on individual parameter estimates from a population pharmacokinetic analysis of 53 pediatric patients with SLE (Trial 6). Following IV 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 SLE. Steady-state geometric mean Cmax, Cmin, Cavg, and AUC values were 305, 42, 92 mcg/mL, and 2,569 day•mcg/mL in the 5- to 11-year-old group, and 317, 52, 112 mcg/mL and 3,126 day•mcg/mL in the 12- to 17-year-old group. [See Use in Specific Populations (8.4).]

For active lupus nephritis, the pharmacokinetics of belimumab in pediatric patients were estimated based on a population pharmacokinetic model developed from 224 adults with active lupus nephritis and validated using data from 53 pediatric patients with SLE. With IV 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- to 11-year-old group and the 12- to 17-year-old group were estimated to be comparable to 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 patients. 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 based on weight or BMI for subcutaneous administration.

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 patients 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 patients with mild renal impairment, 261 patients with moderate renal impairment, and 14 patients with severe renal impairment received belimumab intravenously; 121 patients with mild renal impairment and 30 patients 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.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of BENLYSTA or of other belimumab products.

In Trials 2 and 3 (intravenous dosing in adults with SLE), anti-belimumab antibodies were assessed during the respective 52-week and 76-week, placebo-controlled periods and detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions were life-threatening. In Trial 4 (intravenous dosing in adult Black patients), anti-belimumab antibodies were detected in 2 of 321 (0.6%) patients receiving BENLYSTA 10 mg/kg during the 52-week, placebo-controlled period. In Trial 5 (intravenous dosing in adults with lupus nephritis), there was no formation of anti-belimumab antibodies in 224 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 104-week, placebo‑controlled period. In Trial 6 (intravenous dosing in pediatric patients with SLE), there was no formation of anti-belimumab antibodies in 53 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 52-week, placebo‑controlled period. In Trial 7 (subcutaneous dosing in adults with SLE), there was no formation of anti‑belimumab antibodies in 556 patients receiving BENLYSTA 200 mg during the 52-week, placebo-controlled period.

The clinical relevance of the presence of anti-belimumab antibodies is not known.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab.

Effects on male and female fertility have not been directly evaluated in animal studies.

14.1 Intravenous Administration in Adults with SLE

Trial 1: SLE – BENLYSTA 1 mg/kg, 4 mg/kg, 10 mg/kg - Intravenous

Trial 1 enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg BENLYSTA plus standard therapy compared with placebo plus standard therapy over 52 weeks in patients with SLE. Patients had to have a Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of >4 at baseline and a history of autoantibodies (anti-nuclear antibody [ANA] and/or anti–double-stranded DNA [anti-dsDNA]), but 28% of the population was autoantibody negative at baseline. The co-primary endpoints were percent change in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No significant differences between any of the groups receiving BENLYSTA and the group receiving placebo were observed. Exploratory analysis of this trial identified a subgroup of patients (72%) who were autoantibody positive in whom BENLYSTA appeared to offer benefit. The results of this trial informed the design of Trials 2 and 3 and led to the selection of a target population and indication that is limited to autoantibody-positive SLE patients.

Trials 2, 3 and 4: SLE – BENLYSTA 1 mg/kg and 10 mg/kg - Intravenous

Trials 2 and 3 were randomized, double‑blind, placebo‑controlled trials in patients with SLE that were similar in design except duration; Trial 2 (N = 819) was 76 weeks’ duration and Trial 3 (N = 865) was 52 weeks’ duration. Patients had active SLE disease with a SELENA‑SLEDAI score ≥6 and positive autoantibody test results at screening. Patients were excluded from the trial if they had ever received treatment with a B‑cell-targeted agent or if they were currently receiving other biologic agents. Intravenous cyclophosphamide was not permitted within the previous 6 months or during the trial. Trial 2 was conducted primarily in North America and Europe. Trial 3 was conducted in South America, Eastern Europe, Asia, and Australia.

Baseline concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%), immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine, methotrexate, and mycophenolate), and antimalarials (Trial 2: 63%, Trial 3: 67%). Most patients (>70%) were receiving 2 or more classes of SLE medications.

In Trial 2 and Trial 3, more than 50% of patients had 3 or more active organ systems involved at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (82% in both trials), immune (Trial 2: 74%, Trial 3: 85%), and musculoskeletal (Trial 2: 73%, Trial 3: 59%). Less than 16% of patients had some degree of renal activity and less than 7% of patients had activity in the vascular, cardio-respiratory, or CNS systems.

At screening, patients were stratified by disease severity based on their SELENA‑SLEDAI score (≤9 vs. ≥10), proteinuria level (<2 g/24 h vs. ≥2 g/24 h), and race (African or Indigenous-American descent vs. other), and then randomly assigned to receive BENLYSTA 1 mg/kg, BENLYSTA 10 mg/kg, or placebo in addition to standard therapy. The patients were administered trial medication intravenously over a 1‑hour period on Days 0, 14, 28, and then every 28 days for 48 weeks in Trial 3 and for 72 weeks in Trial 2.

The primary efficacy endpoint was a composite endpoint (SLE Responder Index-4 or SRI-4) that defined response as meeting each of the following criteria at Week 52 compared with baseline:

•

≥4‑point reduction in the SELENA‑SLEDAI score, and

•

no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and

•

no worsening (<0.30‑point increase) in Physician’s Global Assessment (PGA) score.

The SRI uses the SELENA‑SLEDAI score as an objective measure of reduction in global disease activity; the BILAG index to ensure no significant worsening in any specific organ system; and the PGA to ensure that improvements in disease activity are not accompanied by worsening of the patient’s condition overall.

In both Trials 2 and 3, the proportion of patients with SLE achieving an SRI-4 response, as defined for the primary endpoint, was significantly higher in the group receiving BENLYSTA 10 mg/kg plus standard therapy than in the group receiving placebo plus standard therapy. The effect on the SRI-4 was not consistently significantly different for patients receiving BENLYSTA 1 mg/kg plus standard therapy relative to placebo plus standard therapy in both trials. The 1-mg/kg dose is not recommended. The trends in comparisons between the treatment groups for the rates of response for the individual components of the endpoint were generally consistent with that of the SRI-4 (Table 4). At Week 76 in Trial 2, the SRI-4 response rate with BENLYSTA 10 mg/kg was not significantly different from that of placebo (39% and 32%, respectively).

The reduction in disease activity seen in the SRI-4 was related primarily to improvement in the most commonly involved organ systems; namely, mucocutaneous, musculoskeletal, and immune.

Effect in Black/African-American Patients: In Trials 2 and 3, exploratory sub-group analyses of SRI-4 response rate in Black patients (n = 148) were performed. The SRI-4 response rate in Black patients in groups receiving BENLYSTA plus standard therapy was less than that in the group receiving placebo plus standard therapy (22/50 or 44% for placebo, 15/48 or 31% for BENLYSTA 1 mg/kg, and 18/50 or 36% for BENLYSTA 10 mg/kg).

Trial 4 was a 2:1 randomized, placebo-controlled trial in Black patients with SLE (N = 448) conducted in North America, South America, Europe, and Africa (same study design as Trials 2 and 3 with exceptions of patients having a baseline SELENA-SLEDAI score of >8 and using the modified SLEDAI-2K scoring for proteinuria). The population had a mean age of 39 years (range: 18 to 71) and 97% were female. The proportion of Black patients achieving an SRI-S2K response at Week 52 (primary endpoint), and the individual components of the endpoint, were higher in the group receiving BENLYSTA 10 mg/kg plus standard therapy relative to the group receiving placebo plus standard therapy. However, the treatment difference was not statistically significant (Table 5).

Effect on Concomitant Steroid Treatment: In Trial 2 and Trial 3, 46% and 69% of patients, respectively, were receiving prednisone at doses >7.5 mg/day at baseline. The proportion of patients able to reduce their average prednisone dose by at least 25% to ≤7.5 mg/day during Weeks 40 through 52 was not consistently significantly different for BENLYSTA plus standard therapy relative to placebo plus standard therapy in both trials. In Trial 2, 17% of patients receiving BENLYSTA 10 mg/kg plus standard therapy and 19% of patients receiving BENLYSTA 1 mg/kg plus standard therapy achieved this level of steroid reduction compared with 13% of patients receiving placebo plus standard therapy. In Trial 3, 19%, 21%, and 12% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg, and placebo, respectively, plus standard therapy achieved this level of steroid reduction.

Effect on Severe SLE Flares: The probability of experiencing a severe SLE flare, as defined by a modification of the SELENA Trial flare criteria, which excluded severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated for both Trials 2 and 3. The proportion of patients having at least 1 severe flare over 52 weeks was not consistently significantly different for BENLYSTA plus standard therapy relative to placebo plus standard therapy in both trials. In Trial 2, 18% of patients receiving BENLYSTA 10 mg/kg plus standard therapy and 16% of patients receiving BENLYSTA 1 mg/kg plus standard therapy had a severe flare compared with 24% of patients receiving placebo plus standard therapy. In Trial 3, 14%, 18%, and 23% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg and placebo, respectively, plus standard therapy had a severe flare.

14.2 Intravenous Administration in Adults with Lupus Nephritis

Trial 5: Lupus Nephritis – BENLYSTA 10 mg/kg - Intravenous

The safety and effectiveness of BENLYSTA 10 mg/kg administered intravenously over 1 hour on Days 0, 14, 28, and then every 28 days plus standard therapy were evaluated in a 104-week, randomized, double‑blind, placebo‑controlled trial in 448 patients with active proliferative and/or membranous lupus nephritis (Trial 5). The patients had a clinical diagnosis of SLE according to American College of Rheumatology classification criteria; biopsy-proven lupus nephritis Class III, IV, and/or V; and had active renal disease at screening requiring standard therapy: corticosteroids with 1) mycophenolate for induction followed by mycophenolate for maintenance, or 2) cyclophosphamide for induction followed by azathioprine for maintenance. This trial was conducted in Asia, North America, South America, and Europe. The mean age of patients was 33 years (range: 18 to 77); the majority (88%) were female.

The primary efficacy endpoint was Primary Efficacy Renal Response (PERR) at Week 104, defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: urine protein:creatinine ratio (uPCR) ≤0.7 g/g and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 or no decrease in eGFR of >20% from pre-flare value.

The major secondary endpoints included:

•

Complete Renal Response (CRR) defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: uPCR <0.5 g/g and eGFR ≥90 mL/min/1.73 m2 or no decrease in eGFR of >10% from pre-flare value.

•

PERR at Week 52.

•

Time to renal-related event or death (renal-related event defined as first event of end-stage renal disease, doubling of serum creatinine, renal worsening [defined by quantified increase in proteinuria and/or impaired renal function], or receipt of renal disease-related prohibited therapy due to inadequate lupus nephritis control or renal flare management).

The proportion of patients achieving PERR at Week 104 was significantly higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy (Table 6). The major secondary endpoints also showed significant improvement with BENLYSTA plus standard therapy compared with placebo plus standard therapy (Table 6 and Table 7).

In descriptive subgroup analyses, the PERR and CRR rates were examined by induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V), and uPCR levels at baseline (<3 g/g or ≥3 g/g; post-hoc analysis) (Figure 1).

Figure 1. Odds Ratio of PERR and CRR at Week 104 across Subgroupsa, b (Trial 5)

a Class III = Focal proliferative lupus nephritis; Class IV = Diffuse proliferative lupus nephritis; Class V = Membranous lupus nephritis; Class III + V = Mixed membranous-focal proliferative lupus nephritis; Class IV + V = Mixed membranous-diffuse proliferative lupus nephritis.

b Baseline urine protein:creatinine ratio (uPCR) was a post-hoc analysis.

The proportion of responders for PERR by visit through Week 104 is shown in Figure 2.

Figure 2. Primary Efficacy Renal Response (PERR) in Adults with Lupus Nephritis (+/- Standard Error) by Visita (Trial 5)

a Analysis is descriptive; bars represent standard error. The same patients may not have responded at each timepoint.

In Trial 5, subjects who received BENLYSTA were significantly less likely to experience a renal-related event or death compared with placebo (Table 7).

In descriptive subgroup analyses of time to renal-related event or death, results were consistent with the overall endpoint regardless of induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V; post-hoc analysis), and baseline proteinuria (<3 g/g or ≥3 g/g; post-hoc analysis). The treatment difference was primarily driven by the renal worsening and renal-related treatment failure components of the endpoint.

14.3 Intravenous Administration in Pediatric Patients with SLE

Trial 6: SLE – BENLYSTA 10 mg/kg in Pediatric Patients - Intravenous

The safety and efficacy of BENLYSTA was evaluated in an international, randomized, double-blind, placebo‑controlled, 52-week, pharmacokinetics (PK), efficacy and safety study conducted in 93 pediatric patients with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Patients had active SLE disease, defined as a SELENA-SLEDAI score ≥6 and positive autoantibodies at screening as defined in the adult trials. Patients were on a stable SLE treatment regimen (standard of care) and had similar inclusion and exclusion criteria as in the adult studies. The median age was 15 years (range: 6 to 17). The majority (95%) of patients were female. More than 50% of patients had 3 or more active organ systems involved at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (91%), immunologic (74%), and musculoskeletal (73%). Overall, 19% of pediatric patients had some degree of renal activity and less than 7% had activity in the cardio-respiratory, hematologic, CNS or vascular systems. Randomization into age-related treatment cohorts was stratified by screening SELENA-SLEDAI scores (6 to 12 vs >13) and age (5 to 11 years vs 12 to 17 years).

The primary efficacy endpoint was the SLE Responder Index (SRI-4) at Week 52, as described in the adult intravenous trials. There was a numerically higher proportion of pediatric patients achieving a response in SRI‑4 and its components in pediatric patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy (Table 8).

Effect on Concomitant Steroid Treatment: At baseline, 95% of pediatric patients were receiving prednisone. Among those pediatric patients, 20% of pediatric patients receiving BENLYSTA plus standard therapy reduced their average prednisone dose by at least 25% per day during Weeks 44 through 52 compared with 21% of pediatric patients on placebo plus standard therapy.

Effect on Severe SLE Flares: In Trial 6, the probability of experiencing a severe SLE flare, as measured by the modified SELENA-SLEDAI Flare Index, excluding severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated. The proportion of pediatric patients reporting at least one severe flare during the study was numerically lower in pediatric patients receiving BENLYSTA plus standard therapy (17%) compared with those receiving placebo plus standard therapy (35%). Pediatric patients receiving BENLYSTA 10 mg/kg plus standard therapy had a 64% lower risk of experiencing a severe flare during the 52 weeks of observation, relative to the placebo plus standard therapy group. Of the pediatric patients experiencing a severe flare, the median time to the first severe flare was 150 days in pediatric patients receiving BENLYSTA plus standard therapy compared with 113 days in pediatric patients receiving placebo plus standard therapy.

14.4 Subcutaneous Administration in Adults with SLE

Trial 7: SLE – BENLYSTA 200 mg - Subcutaneous

The safety and effectiveness of BENLYSTA administered subcutaneously were evaluated in a randomized, double‑blind, placebo‑controlled trial involving 836 adult patients with SLE according to the American College of Rheumatology criteria (Trial 7, NCT01484496). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. The trial (2:1 randomization) evaluated BENLYSTA 200 mg once weekly plus standard therapy (n = 556) compared with placebo once weekly plus standard therapy (n = 280) over 52 weeks in patients with active SLE disease. Patients had to have a SELENA-SLEDAI score of ≥8 and positive autoantibody test (anti-nuclear antibody [ANA] and/or anti–double-stranded DNA [anti-dsDNA]) results at screening.

No significant differences in baseline patient characteristics were observed between treatment groups. In some countries, treatment with a B-cell-targeted agent was permitted if received a year or more prior to baseline; otherwise, treatment with a B-cell-targeted agent was not permitted. Patients were excluded from the trial if they were currently receiving other biologic agents. Anti-tumor necrosis factor therapy, intravenous cyclophosphamide, interleukin-1 receptor antagonist, intravenous immunoglobulin (IVIG), prednisone >100 mg/day, and plasmapheresis were not permitted within the previous 3 months or during the trial. The trial was conducted in North America, South America, Europe, and Asia. Baseline concomitant medications included corticosteroids (86%), antimalarials (69%), and immunosuppressives (46%, including azathioprine, methotrexate, and mycophenolate). Most patients (approximately 80%) were receiving 2 or more classes of SLE medications.

More than 50% of patients had 3 or more active organ systems involved at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (88%), musculoskeletal (78%), and immunologic (76%). Overall, 12% of patients had some degree of renal activity and less than 15% of patients had activity in the vascular, cardio-respiratory, or CNS systems. Patients were stratified by disease severity based on their SELENA-SLEDAI score (≤9 vs. ≥10), complement level (C3 and/or C4 low vs. other), and race (Black vs. other), and then randomly assigned to receive BENLYSTA 200 mg plus standard therapy or placebo once weekly plus standard therapy.

The primary efficacy endpoint was the SLE Responder Index-4 (SRI-4) at Week 52 as described in the intravenous trials. Secondary efficacy endpoints included time to first severe flare (as measured by the modified SELENA-SLEDAI SLE Flare Index) and the proportion of patients receiving prednisone >7.5 mg/day at baseline whose average prednisone dose had been reduced by ≥25% to ≤7.5 mg/day during Weeks 40 through 52.

The proportion of patients achieving an SRI-4 response was significantly higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. The trends comparing the treatment groups with respect to the probability of response for the individual components of the endpoint were consistent with that of the SRI-4 (Table 9).

The reduction in disease activity seen in the SRI-4 was related primarily to improvement in the most commonly involved organ systems, namely, mucocutaneous, musculoskeletal, immunologic, and vascular.

The proportion of SRI-4 responders by visit through Week 52 is shown in Figure 3.

Figure 3. Proportion (%) of SRI-4 Responders (+/- Standard Error) by Visita

a The same patients may not have responded at each timepoint.

Effect in Black/African-American Patients: Exploratory sub-group analyses of SRI-4 response rate in Black patients (n = 91) were performed. The SRI-4 response rate in Black patients receiving BENLYSTA plus standard therapy was 45% (26/58) compared with 39% (13/33) in the group receiving placebo plus standard therapy [see Use in Specific Populations (8.8)].

Effect on Concomitant Steroid Treatment: At baseline, 60% of patients were receiving prednisone at doses >7.5 mg/day. Among these patients, 18% of patients receiving BENLYSTA plus standard therapy reduced their average prednisone dose by at least 25% to ≤7.5 mg/day during Weeks 40 through 52 compared with 12% of patients on placebo plus standard therapy; this difference was not statistically significant (OR = 1.65 [95% CI: 0.95, 2.84]).

Effect on Severe SLE Flares: The probability of experiencing a severe SLE flare, as measured by the modified SELENA-SLEDAI SLE Flare Index, excluding severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated. The proportion of patients reporting at least 1 severe flare during the study was lower in patients treated with BENLYSTA plus standard therapy (11%) compared with those receiving placebo plus standard therapy (18%). Patients treated with BENLYSTA plus standard therapy had a 49% lower risk of experiencing at least 1 severe flare during the 52 weeks of observation, relative to the patients receiving placebo plus standard therapy (HR = 0.51 [95% CI: 0.35, 0.74]). Of the patients experiencing a severe flare, the median time to the first severe flare was delayed in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy (171 days vs. 118 days).

16.1 Intravenous Infusion

BENLYSTA (belimumab) for injection is a sterile, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous infusion provided in single‑dose glass vials with a rubber stopper (not made with natural rubber latex) and a flip‑off seal. Each 5‑mL vial contains 120 mg of belimumab. Each 20‑mL vial contains 400 mg of belimumab.

BENLYSTA vials are supplied as follows:

120 mg belimumab in a 5-mL single-dose vial (NDC 49401-101-01)

400 mg belimumab in a 20-mL single-dose vial (NDC 49401-102-01)

Refrigerate vials at 36°F to 46°F (2°C to 8°C). Store vials in the original carton until use to protect from light. Do not freeze. Avoid exposure to heat.

16.2 Subcutaneous Injection

BENLYSTA (belimumab) injection is a clear to opalescent, and colorless to pale yellow solution for subcutaneous use. Each single-dose prefilled autoinjector or single-dose prefilled syringe is designed to deliver 200 mg of belimumab in 1 mL of solution and is supplied as follows:

200 mg/mL single-dose prefilled autoinjector with 27-gauge, half-inch needle attached (NDC 49401-088-01) in a carton of 4 (NDC 49401-088-35).

200 mg/mL single-dose prefilled glass syringe with 27-gauge, half-inch needle attached (NDC 49401-088-42) in a carton of 4 (NDC 49401-088-47).

Prior to Dispensing

Refrigerate prefilled autoinjectors and prefilled syringes at 36°F to 46°F (2°C to 8°C). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Avoid exposure to heat.

Following Dispensing

Refrigerate prefilled autoinjectors and prefilled syringes at 36°F to 46°F (2°C to 8°C). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Avoid exposure to heat.

BENLYSTA may be stored outside of the refrigerator up to 86°F (30°C) for up to 12 hours if protected from sunlight. Do not use and do not place back in refrigerator if left out for more than 12 hours.