Belimumab

Belimumab
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]

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Overview

Belimumab is a monoclonal antibody that is FDA approved for the treatment of active, autoantibody-positive, systemic lupus erythematosus. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Belimumab FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belimumab in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belimumab in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Belimumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belimumab in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belimumab in pediatric patients.

Contraindications

BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

Warnings

Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2,133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.

5.2 Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1,458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

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, consider stopping immunosuppressant therapy, including BENLYSTA.

5.3 Malignancy The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the 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. The mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

5.4 Hypersensitivity Reactions, including Anaphylaxis Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. 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. In the controlled clinical trials, 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. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see WARNINGS AND PRECAUTIONS (5.5)]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of an acute hypersensitivity reaction and be instructed to seek immediate medical care should a reaction occur.

5.5 Infusion Reactions In the controlled clinical trials, 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. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see WARNINGS AND PRECAUTIONS (5.4)]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see ADVERSE REACTIONS (6.1)].

BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.

5.6 Depression In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% 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. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if treatment with BENLYSTA is associated with increased risk for these events.

Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

5.7 Immunization 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. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.

5.8 Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.

Adverse Reactions

Clinical Trials Experience

The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2,133 patients in 3 controlled trials. Patients received BENLYSTA at doses of 1 mg/kg (N = 673), 4 mg/kg (N = 111; Trial 1 only), or 10 mg/kg (N = 674) or placebo (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)]. 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 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.

The population had a mean age of 39 (range: 18 to 75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo.

The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions (5.2)].

The most commonly-reported adverse reactions, 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 and 7.1% for patients receiving placebo. 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 1.0% placebo).

TABLE 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.

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Immunogenicity

In Trials 2 and 3, anti-belimumab antibodies were 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 was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.

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

Drug Interactions

ormal drug interaction studies have not been performed with BENLYSTA. In clinical trials of patients with SLE, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and 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

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women. Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment.

Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5, and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24%, and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8%, and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of immunoglobulin M (IgM) in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belimumab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Belimumab during labor and delivery.

Nursing Mothers

It is not known whether BENLYSTA is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of BENLYSTA have not been established in children.

Geriatic Use

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

Gender

There is no FDA guidance on the use of Belimumab with respect to specific gender populations.

Race

In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects receiving BENLYSTA relative to black subjects receiving placebo [see CLINICAL STUDIES (14)]. Use with caution in black/African-American patients.

Renal Impairment

There is no FDA guidance on the use of Belimumab in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Belimumab in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Belimumab in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Belimumab in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Belimumab Administration in the drug label.

Monitoring

There is limited information regarding Belimumab Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Belimumab and IV administrations.

Overdosage

There is no clinical experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

Pharmacology

There is limited information regarding Belimumab Pharmacology in the drug label.

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.

Structure

BENLYSTA (belimumab) is a human IgG1λ monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a mammalian cell expression system.

BENLYSTA is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous infusion. Upon reconstitution with Sterile Water for Injection, USP [see DOSAGE AND ADMINISTRATION (2.3)], each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric acid, 0.4 mg/mL polysorbate 80, 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with a pH of 6.5.

Pharmacodynamics

In Trial 1 and Trial 2 in which B cells were measured, treatment with BENLYSTA significantly reduced circulating CD19+, CD20+, naïve, and activated B cells, plasmacytoid 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 were sustained to Week 52. Memory cells increased initially and slowly declined toward baseline levels by Week 52. The clinical relevance of these effects on B cells has not been established.

Treatment with BENLYSTA led to reductions in IgG and anti-dsDNA, and increases in complement (C3 and C4). These changes were observed as early as Week 8 and were sustained through Week 52. The clinical relevance of normalizing these biomarkers has not been definitively established.

Pharmacokinetics

The pharmacokinetic parameters displayed in TABLE 2 are based on population parameter estimates which are specific to the 563 patients who received BENLYSTA 10 mg/kg in Trials 2 and 3 [see CLINICAL STUDIES (14)].

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Intravenous infusions were administered at 2‑ week intervals for the first 3 doses and at 4‑ week intervals thereafter.

Drug Interactions: No formal drug interaction studies have been conducted with BENLYSTA. Concomitant use of mycophenolate, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and 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.

Special Populations: The following information is based on the population pharmacokinetic analysis.

Age: Age did not significantly influence belimumab pharmacokinetics in the trial population, where the majority of subjects (70%) were aged between 18 and 45 years. No pharmacokinetic data are available in pediatric patients. Limited pharmacokinetic data are available for elderly patients as only 1.4% of the subjects included in the pharmacokinetic analysis were aged 65 years or older [see USE IN SPECIFIC POPULATIONS (8.5)].

Gender: Gender did not significantly influence belimumab pharmacokinetics in the largely (94%) female trial population.

Race: Race did not significantly influence belimumab pharmacokinetics. The racial distribution was 53% white/Caucasian, 16% Asian, 16% Alaska native/American Indian, and 14% black/African-American.

Renal Impairment: No formal trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. BENLYSTA has been studied in a limited number of patients with SLE and renal impairment (261 subjects with moderate renal impairment, creatinine clearance ≥30 and <60 mL/min; 14 subjects with severe renal impairment, creatinine clearance ≥15 and <30 mL/min). Although increases in creatinine clearance and proteinuria (>2 g/day) increased belimumab clearance, these effects were within the expected range of variability. Therefore, dosage adjustment in patients with renal impairment is not recommended.

Hepatic Impairment: No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab. The mutagenic potential of belimumab was not evaluated.

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

Clinical Studies

The safety and effectiveness of BENLYSTA were evaluated in 3 randomized, double-blind, placebo-controlled trials involving 2,133 patients with SLE according to the American College of Rheumatology criteria (Trial 1, 2, and 3). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were on a stable standard of care SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics and intravenous cyclophosphamide were not permitted.

Trial 1: BENLYSTA 1 mg/kg, 4 mg/kg, 10 mg/kg

Trial 1 enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg BENLYSTA plus standard of care compared with placebo plus standard of care over 52 weeks in patients with SLE. Patients had to have a 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 and 3: BENLYSTA 1 mg/kg and 10 mg/kg

Trials 2 and 3 were randomized, double-blind, placebo-controlled trials in patients with SLE that were similar in design except duration - Trial 2 was 76 weeks duration and Trial 3 was 52 weeks duration. Eligible patients had active SLE disease, defined as 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 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 hr vs. ≥2 g/24 hr), 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 of care. 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 or SRI) 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 SLE patients achieving an SRI response, as defined for the primary endpoint, was significantly higher in the group receiving BENLYSTA 10 mg/kg than in the group receiving placebo. The effect on the SRI was not consistently significantly different for patients receiving BENLYSTA 1 mg/kg relative to placebo 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 (Table 3). At Week 76 in Trial 2, the SRI response rate with BENLYSTA 10 mg/kg was not significantly different from that of placebo (39% and 32%, respectively).

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

Effect in Black/African-American Patients: Exploratory sub-group analyses of SRI response rate in patients of black race were performed. In Trial 2 and Trial 3 combined, the SRI response rate in black patients (N = 148) in groups receiving BENLYSTA was less than that in the group receiving placebo (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). In Trial 1, black patients (N = 106) in the groups receiving BENLYSTA did not appear to have a different response than the rest of the trial population. Although no definitive conclusions can be drawn from these subgroup analyses, caution should be used when considering treatment with BENLYSTA in black/African-American SLE patients.

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 relative to placebo in both trials. In Trial 2, 17% of patients receiving BENLYSTA 10 mg/kg and 19% of patients receiving BENLYSTA 1 mg/kg achieved this level of steroid reduction compared with 13% of patients receiving placebo. In Trial 3, 19%, 21%, and 12% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg, and placebo, respectively, 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 relative to placebo in both trials. In Trial 2, 18% of patients receiving BENLYSTA 10 mg/kg and 16% of patients receiving BENLYSTA 1 mg/kg had a severe flare compared with 24% of patients receiving placebo. In Trial 3, 14%, 18%, and 23% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg and placebo, respectively, had a severe flare.

How Supplied

BENLYSTA is a sterile, preservative-free, lyophilized powder for reconstitution, dilution, and intravenous infusion provided in single-use 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 is supplied as follows:

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Storage

Store vials of BENLYSTA refrigerated between 2° to 8°C (36° to 46°F). Vials should be protected from light and stored in the original carton until use. Do not freeze. Avoid exposure to heat. Do not use beyond the expiration date.

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Patient Counseling Information

Advice for the Patient Give patients the Medication Guide for BENLYSTA and provide them an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed.

Mortality: Advise patients that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see WARNINGS AND PRECAUTIONS (5.1)].

Serious Infections: Advise patients that BENLYSTA may decrease their ability to fight infections. Ask patients if they have a history of chronic infections and if they are currently on any therapy for an infection [see WARNINGS AND PRECAUTIONS (5.2)]. Instruct patients to tell their healthcare provider if they develop signs or symptoms of an infection.

Progressive Multifocal Leukoencephalopathy (PML): Advise patients to contact their healthcare professional if they experience new or worsening neurological symptoms such as memory loss, confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of hypersensitivity and infusion reactions, including wheezing, difficulty breathing, angioedema, rash, hypotension, bradycardia, and headache. Instruct patients to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA. Inform patients to tell their healthcare provider about possible reactions that may include a combination of symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial swelling and may occur after administration of BENLYSTA [see WARNINGS AND PRECAUTIONS (5.4, 5.5)].

Depression: Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes [see WARNINGS AND PRECAUTIONS (5.6)].

Immunizations: Inform patients that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA [see WARNINGS AND PRECAUTIONS (5.7)].

Pregnancy and Nursing Mothers: Inform patients that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see USE IN SPECIFIC POPULATIONS (8.1)]. Encourage pregnant patients to enroll in the pregnancy registry for BENLYSTA [see Use in Specific Populations (8.1)]. Instruct patients to tell their healthcare provider if they plan to breastfeed their infant [see USE IN SPECIFIC POPULATIONS (8.3)].

Precautions with Alcohol

Alcohol-Belimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Benlysta

Look-Alike Drug Names

There is limited information regarding Belimumab Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Template:Drugbox-mab Belimumab (registered name LymphoStat-B), is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLys), also known as B cell activation factor of the TNF family (BAFF). It is being developed by Human Genome Sciences Inc. and GlaxoSmithKline. BLyS is a protein necessary for the maturation of B lymphocytes.

Interaction of BLyS with B lymphocytes

BLyS (also known as BAFF) plays a key role in B lymphocyte differentiation, survival and activation. Three membrane receptors are concerned:

• BCMA (B cell maturation antigen)
• TACI (transmembrane activator and calcium modulator and cyclophylin ligand interactor)
• BAFF-R (also known as BR3)

These receptors are not present in early B cell precursors or in pre-B cells (stage at which CD20 receptors appear). They are present in primary mature B cells and in mature B cells (in this last stage, CD20 receptors have disappeared).

BLyS is secreted, sometimes under the influence of interferon-gamma, by a variety of cells: monocytes and macrophages, bone marrow stromal cells, astrocytes, synoviocytes during rheumatoid arthritis, salivary epithelial cells during Sjögren's syndrome, astrocytes in certain glioblastomas.

Lymphocyte apoptosis is decreased because stimulation of BAFF-R and BCMA increases levels of Bcl-2 (a key anti-apoptotic mediator). Stimulation of all 3 receptors increases intranuclear levels of NF kappa B, active on differentiation and proliferation.

BLyS is not the only activator of B lymphocytes. APRIL (a proliferation activating ligand) also plays a key role, but is only active on BCMA and TACI.

Mechanism of action of belimumab

Belimumab is a monoclonal antibody that binds to BlyS. It is possible that belimumab binds essentially to circulating soluble BlyS, therefore not inducing an antibody-dependent cellular cytotoxicity that could be expected from a IgG1-type antibody. Nevertheless, it does reduce the number of circulating B cells, but seemingly less, and for less time, than anti-CD20 monoclonals (this impression was given at the June 2007 European League against Rheumatism symposium). Only comparative trials will clarify this impression.

Diseases with B lymphocyte hyperactivity

B lymphocyte hyperactivity is known in malignant and non-malignant diseases.

Among the malignant diseases (B cell malignancies):

• non-Hodgkin lymphoma
• chronic lymphocytic leukemia
• multiple myeloma

Among the non-malignant diseases:

• Multiple sclerosis
• Rheumatoid arthritis
• Systemic lupus erythematosus - It is in this last field that Belimumab is the most advanced (2 phase 3 trials ongoing, with regulatory filing possibly in 2010).

Other drugs addressing B lymphocyte hyperactivity

Atacicept is a recombinant fusion protein built with the extracellular ligand binding portion of TACI. It blocks activation of TACI by April and BLyS. It is being developed by Zymogenetics and Serono/Merck KgaA. Early stage trials are ongoing in B cell malignancies (Multiple Myeloma), Systemic Lupus Erythematosus and Rheumatoid arthritis.

BR3-Fc is a recombinant fusion protein built with the extracellular ligand-binding portion of BAFF-R. It blocks activation of this receptor by BLys. It is in early stage development by Biogen and Genentech.

Anti-CD20 monoclonals: Rituximab is approved. Ocrelizumab, Ofatumumab and 3rd generation anti CD20 monoclonals are being developed.

References

• Bossen C, Schneider P (2006). "BAFF, APRIL and their receptors: structure, function and signaling". Semin. Immunol. 18 (5): 263–75. doi:10.1016/j.smim.2006.04.006. PMID 16914324.