2.1 Dosage Schedule

BENLYSTA is for intravenous infusion only and must be reconstituted and diluted prior to administration [see Dosage and Administration (2.3)]. Do not administer as an intravenous push or bolus.

The recommended dosage regimen 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 only, over a period of 1 hour. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion must be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Contraindications (4), Warnings and Precautions (5.4)].

2.2 Premedication Recommendations

Prior to dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions. [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6.1)].

2.3 Preparation of Solutions

BENLYSTA is provided as a lyophilized powder in a single-use vial for intravenous infusion only and should be reconstituted and diluted by a healthcare professional using aseptic technique as follows:

Reconstitution Instructions

1.

Remove BENLYSTA from the refrigerator and allow to stand 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

6.

Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP. Dilute the reconstituted product to 250 mL in 0.9% Sodium Chloride Injection, USP (normal saline) for intravenous infusion. From a 250-mL infusion bag or bottle of normal saline, 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 infusion bag or bottle. Gently invert the bag or bottle to mix the 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 2° to 8°C (36° to 46°F). Solutions of BENLYSTA diluted in normal saline may be stored at 2° to 8°C (36° to 46°F) 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.

2.4 Administration Instructions

1.

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

2.

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. [see Warnings and Precautions (5.4)]

3.

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.

5.1 Mortality

There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 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 placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, 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 BENLYSTA therapy 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% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

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% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

5.4 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. 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% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) 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 a hypersensitivity reaction and 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% (251/1458) 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% (6/1458) 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 BENLYSTA treatment 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.

6.1 Clinical Trials Experience

The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2133 patients in 3 controlled studies. 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 two of the studies (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other study (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 – 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.

6.2 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.

6.3 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 Warnings and Precautions (5.4)].

8.1 Pregnancy

Pregnancy Category 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 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 Registry: To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

8.3 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.

8.4 Pediatric Use

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

8.5 Geriatric 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.

8.6 Race

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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

Drug Interactions: No formal drug interaction studies have been conducted with belimumab. 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 study population, where the majority of subjects (70%) were between 18 and 45 years of age. 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 65 years of age or older [see Use in Specific Populations (8.5)].

Gender: Gender did not significantly influence belimumab pharmacokinetics in the largely (94%) female study 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 studies were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. Belimumab 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 studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Belimumab has not been studied in patients with severe hepatic impairment. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics.

13.1 Carcinogenesis, Mutagenesis, and 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.

17.1 Advice for the Patient

Patients should be given the Medication Guide for BENLYSTA and provided 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: Patients should be advised 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: Patients should be advised that BENLYSTA may decrease their ability to fight infections. Patients should be asked 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)]. Patients should be instructed to tell their healthcare provider if they develop signs or symptoms of an infection.

Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of anaphylaxis, including wheezing, difficulty breathing, peri-oral or lingual edema, and rash. Patients should be instructed to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA [see Warnings and Precautions (5.4, 5.5)].

Depression: Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes [seeWarnings and Precautions (5.6)].

Immunizations: Patients should be informed 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: Patients should be informed 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. Patients should be instructed to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations (8.1)]. Patients should be instructed to tell their healthcare provider if they plan to breastfeed their infant [seeUse in Specific Populations (8.3)].

BENLYSTA is a registered trademark of Human Genome Sciences, Inc., used under license by GlaxoSmithKline.

Manufactured by:

Human Genome Sciences, Inc.

Rockville, Maryland 20850

US License No. 1820

Marketed by:

Human Genome Sciences, Inc.

Rockville, MD 20850

GlaxoSmithKline

Research Triangle Park, NC 27709

©2011, Human Genome Sciences, Inc. All rights reserved.