BENLYSTA (belimumab) is indicated for the treatment of:

·       patients aged 5 years and older with active, systemic lupus erythematosus (SLE) who are receiving standard therapy, and

·        patients aged 5 years and older with 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.

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).

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, Special warnings and precautions for use).

Precautions Prior to Intravenous Use

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis [see Special warnings and precautions for use, Undesirable effects].

Prior to intravenous dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions (see Special warnings and precautions for use, Undesirable effects).

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.

·       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.     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:

6.     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.

7.     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.

8.     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.

9.     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.

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 Undesirable effects].

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.

Hypersensitivity Reactions, including Anaphylaxis

Acute hypersensitivity reactions, including anaphylaxis and death, and infusion-related reactions have been reported in association with BENLYSTA [see Undesirable effects]. 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 Posology and method of administration).

Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should a reaction occur.

Depression and Suicidality

In controlled clinical trials, depression and suicidality were reported in patients receiving BENLYSTA, (see Undesirable effects).

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.

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 Undesirable effects).

 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.

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.

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 Undesirable effects)]. 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 Special warnings and precautions for use).

Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, cyclophosphamide, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG‑CoA reductase inhibitors (statins), and/or non-steroidal anti-inflammatory drugs (NSAIDs) without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated (see Pharmacological properties).

Pregnancy

Risk Summary

Available data on use of BENLYSTA in pregnant women, from observational studies, published case reports, and post-marketing 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 Pharmacological properties).

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 Special warnings and precautions for use).

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.

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.

Contraception in males and females

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.

There have been no studies to investigate the effect of BENLYSTA on driving performance or the ability to operate machinery.  No detrimental effects on such activities are predicted from the pharmacology of BENLYSTA.  

The clinical status of the patient and the safety profile of BENLYSTA should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.

4.8.1 Adverse Reactions

The following serious adverse reactions are described below in the Special warnings and precautions for use section:

·       Serious Infections (see Special warnings and precautions for use).

·       Hypersensitivity Reactions, including Anaphylaxis (see Special warnings and precautions for use).

·       Depression and Suicidality (see Special warnings and precautions for use).

·       Malignancy (see Special warnings and precautions for use).

4.8.2 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). 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 ³5% 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).

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Adult Patients with SLE Treated with BENLYSTA 10 mg/kg plus Standard Therapy and at Least 1% More Frequently than in Patients Receiving Placebo plus Standard Therapy

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, post marketing 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, post marketing 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).

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). 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).

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%).

4.8.3 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.

·       Fatal anaphylaxis [see Special Warnings and Precautions for use].

Use in Specific Populations

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). Pharmacokinetics were evaluated in a total of 53 pediatric patients with SLE and were consistent with the adult population with SLE [see Pharmacokinetic properties].

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 Pharmacokinetic properties].

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.

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.

Renal Impairment

The safety and efficacy of BENLYSTA were evaluated in studies that included patients with SLE who had mild (creatinine clearance [CrCl] ³60 and <90 mL/min), moderate (CrCl ³30 and <60 mL/min), or severe (CrCl ³15 and <30 mL/min) renal impairment. No dosage adjustment is recommended in patients with renal impairment.

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.

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).

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).

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).

The safety profile of BENLYSTA in Black patients was consistent with the known safety profile of BENLYSTA administered in the overall population (see Undesirable effects).

To report any side effect(s):

Kingdom of Saudi Arabia

-National Pharmacovigilance centre (NPC)

·       Reporting Hotline: 19999

·       E-mail: npc.drug@sfda.gov.sa

·       Website: https://ade.sfda.gov.sa

GSK- Head Office, Jeddah

·       Tel:  +966-12-6536666

·       Mobile: +966-56-904-9882

·       Email: saudi.safety@gsk.com 

·       Website: https://gskpro.com/en-sa/

·       P.O. Box 55850, Jeddah 21544, Saudi Arabia

For any information about this medicinal product, please contact:

GSK- Head Office, Jeddah

·       Tel:  +966-12-6536666

·       Mobile: +966-56-904-9882

·       Email: gcc.medinfo@gsk.com

·       Website: https://gskpro.com/en-sa/

·       P.O. Box 55850, Jeddah 21544, Saudi Arabia

There is limited experience with overdosage of belimumab. Adverse reactions reported in association with cases of overdose have been consistent with those expected for belimumab.

Two doses of up to 20 mg/kg have been given intravenously to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

ATC Code 

L04AA26

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.

Pharmacodynamic Effect

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.

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.

Table 2. Population Pharmacokinetic Parameters in Adult Patients with 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.

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) 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.

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).

Pediatric Patients: The pharmacokinetic parameters are based on individual parameter of belimumab 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 C_max, C_min, C_avg, 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).

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).

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 ³60 and <90 mL/min), moderate (CrCl ³30 and <60 mL/min), or severe (CrCl ³15 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).

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).

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.

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.

CLINICAL STUDIES

The safety and effectiveness of BENLYSTA administered intravenously plus standard therapy were evaluated in 4 randomized, double‑blind, placebo‑controlled trials involving 2,581 adult patients with SLE (Trial 1, NCT 00071487, Trial 2, NCT 00410384, Trial 3, NCT 00424476, and Trial 4 NCT 01632241), and one trial involving 93 pediatric patients (Trial 6, NCT 01649765) with SLE according to the American College of Rheumatology criteria. In these trials, patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were on a stable standard therapy SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics and intravenous cyclophosphamide was not permitted.

In addition, the safety and effectiveness of BENLYSTA administered intravenously plus standard therapy was evaluated in a randomized, double‑blind, placebo‑controlled trial in 448 adult patients with active lupus nephritis (Trial 5; NCT 01639339).

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 ³6 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. ³10), proteinuria level (<2 g/24 h vs. ³2 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:

·       ³4‑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 3). 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).

Table 3. Clinical Response Rate in Patients with SLE after 52 Weeks of Treatment

^a  The 1-mg/kg dose is not recommended.

^b  Patients dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. In both trials, a higher proportion of placebo patients were considered as failures for this reason compared with the groups receiving BENLYSTA.

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 4).

Table 4. Clinical Response Rate in Black Patients with SLE after 52 Weeks of Treatment (Trial 4)

^a  Analyses excluded any subject missing a baseline assessment for any of the components (1 for belimumab).

^b  Patients dropping out of the trial early or experiencing certain increases in background medication were considered as failures in these analyses. A higher proportion of patients receiving placebo were considered as failures for this reason compared with the group receiving BENLYSTA.

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.

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 5). The major secondary endpoints also showed significant improvement with BENLYSTA plus standard therapy compared with placebo plus standard therapy (Table 5 and Table 6).

Table 5. Efficacy Results in Adults with Lupus Nephritis (Trial 5) 

eGFR = Estimated glomerular filtration rate.

^a  PERR at Week 104 was the primary efficacy analysis; CRR at Week 104 and PERR at Week 52 were included in pre-specified testing hierarchy.

^b  In order to be considered a responder, steroid treatment had to be reduced to ≤10 mg/day from Week 24. Patients who discontinued treatment early, received prohibited medication or increases in background standard therapy, or withdrew from the study were considered non-responders. Prohibited medications and increases in background standard therapy were defined as: 1) use of corticosteroids above that allowed by protocol; 2) additional immunosuppressive agents (except topicals) beyond their induction/maintenance regimens; 3) angiotensin converting enzyme inhibitors (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or antimalarials initiated after Week 24; 4) exceeding protocol-permitted doses for standard therapy (cyclophosphamide, azathioprine, mycophenolate); or 5) other biologics, IV immunoglobulin, or plasmapheresis.

^c  The percentage of patients who did not take prohibited medications or have an increase in background standard therapy at Week 104 was 83% for BENLYSTA and 74% for placebo.

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 Subgroups^{a, 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 Visit^a (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 6).

Table 6. Time to Renal-Related Event or Death in Adults with Lupus Nephritis (Trial 5) 

^a  Time to renal-related event or death included in pre-specified testing hierarchy.

^b  When excluding deaths from analysis (1 for BENLYSTA; 2 for placebo), the percentage of patients with a renal-related event was 15% for BENLYSTA compared with 27% for placebo (HR = 0.5; 95% CI: 0.3, 0.8).

^c  Subjects who discontinued treatment, were withdrawn from the study, lost to follow-up, or had a treatment failure not related to renal disease were censored on the date of the event. Subjects who completed the 104-week treatment period were censored at the Week 104 visit. Time to event was defined as (event date minus treatment start date plus 1 day).

^d Patients could have had more than one event; the first event contributed to the overall endpoint.

^e  Renal worsening was prospectively defined as the development of increased proteinuria and/or impaired renal function defined as: 1) Increased proteinuria (using spot urine): a reproducible increase in 24-hour urine protein levels to >1 g/g if the baseline value was <0.2 g/g or >2 g/g if the baseline value was between 0.2 g/g and 1 g/g or more than twice the value at baseline if the baseline value was >1 g/g; and 2) Impaired renal function: a reproducible decrease in eGFR of >20% accompanied by at least 1 of the following: proteinuria (>1 g/g), red blood cell casts, or white blood cell casts.

^f  Renal-related treatment failure was prospectively defined as intake of prohibited medications for adjudicated inadequate lupus nephritis control or renal flare management.

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.

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 7).

Table 7. Pediatric Response Rate at Week 52^a (Trial 6) 

^a  Based on a non-powered trial.

^b  Analyses excluded any subject missing a baseline assessment for any of the components (1 for placebo).

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.

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.

Citric acid monohydrate

Sodium citrate dihydrate

Sucrose

Polysorbate 80

BENLYSTA is not compatible with 5% dextrose.

BENLYSTA must be prepared and administered only as directed, see Special precautions for disposal and other handling.

Unopened vials

Store at between 2°C and 8°C.

Do not freeze.

Protect from light. Store in the original carton until use.

Reconstituted solution

After reconstitution with Water for Injections, and dilution in 0.9% sodium chloride (normal saline), 0.45% sodium chloride (half normal saline), or Lactated Ringer’s solution, the product is stable for up to 8 hours at 2°C to 8°C or at room temperature. Protect from direct sunlight.

5 mL Type 1 glass vial sealed with a latex-free siliconised rubber stopper and a flip-off seal containing 120 mg BENLYSTA as a lyophylised powder. 

20 mL Type 1 glass vial sealed with a latex-free siliconised rubber stopper and a flip-off seal containing 400 mg BENLYSTA as a lyophylised powder. 

The drug is supplied in a single use vial without a preservative. 

BENLYSTA is not compatible with 5% dextrose.

Belimumab lyophilised powder for intravenous infusion must be prepared and administered only as directed, see Special precautions for disposal and other handling.

Reconstitution and dilution

BENLYSTA does not contain a preservative; therefore, reconstitution and dilution must be carried out under aseptic conditions.

Allow 10 to 15 minutes for the vial to warm to room temperature.

It is recommended that a 21-25 gauge needle be used when piercing the vial stopper for reconstitution and dilution.

The 120 mg single-use vial of BENLYSTA should be reconstituted with 1.5 mL of sterile Water for Injections to yield a final concentration of 80 mg/mL belimumab. The 400 mg single-use vial of BENLYSTA should be reconstituted with 4.8 mL of sterile Water for Injections to yield a final concentration of 80 mg/mL belimumab.

The stream of sterile water should be directed toward the side of the vial to minimise 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 five 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 direct sunlight.

If a mechanical reconstitution device is used to reconstitute BENLYSTA it should not exceed 500 rpm and the vial should be swirled for no longer than 30 minutes.

Once reconstitution is complete, the solution should be opalescent and colourless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable.

The reconstituted product is diluted to 250 mL with 0.9% sodium chloride (normal saline), 0.45% sodium chloride (half normal saline) or Lactated Ringer’s solution for intravenous infusion. For patients whose body weight is less than or equal to 40 kg, infusion bags with 100 mL normal saline, half normal saline or Lactated Ringer’s solution may be considered providing that the resulting belimumab concentration in the infusion bag does not exceed 4 mg/mL.

5% Dextrose intravenous solutions are incompatible with BENLYSTA and should not be used. 

From a 250 mL (or 100 mL) infusion bag or bottle of normal saline, half normal saline, or Lactated Ringer’s solution, withdraw and discard a volume equal to the volume of the reconstituted BENLYSTA solution required for the patient’s dose. Then add the required volume of the reconstituted BENLYSTA solution into the infusion bag or bottle. Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.

Inspect the BENLYSTA solution visually for particulate matter and discoloration prior to administration. Discard the solution if any particulate matter or discoloration is observed.

The reconstituted solution, if not used immediately, should be protected from direct sunlight and stored refrigerated at 2°C to 8°C.  Solutions diluted in normal saline, half normal saline, or Lactated Ringer’s solution may be stored at 2°C to 8°C or room temperature.

The total time from reconstitution of BENLYSTA to completion of infusion should not Exceed eight hours.

Administration

BENLYSTA should be infused over a 1-hour period.

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 co-administration of BENLYSTA with other agents.

No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags

have been observed.