Belimumab

Class: Immunosuppressive Agents
Chemical Name: Disulfure with human monoclonal LymphoStatB lambda-chain anti-(human cytokine BAFF) (human monoclonal LymphoStatB heavy chain) immunoglobulin G1dimer
Molecular Formula: C6714H10428N1816O2102S52
CAS Number: 356547-88-1
Brands: Benlysta

Introduction

Immunosuppressive agent; recombinant fully human IgG1 lambda monoclonal antibody that inhibits soluble B-lymphocyte stimulator (BLyS).1 3 4 5

Uses for Belimumab

Systemic Lupus Erythematosus

Management of active, autoantibody-positive systemic lupus erythematosus (SLE).1 3 4 7 8 11 12 13 Appears to modestly reduce disease activity in patients with severe autoantibody-positive SLE.11 12 13

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Herbal and Dietary Supplements Deserve Your Attention

Not recommended in patients with severe active lupus nephritis or severe active CNS lupus.1

Efficacy in black patients remains to be definitively established.1 11 (See Blacks under Cautions.)

Use in conjunction with other standard SLE therapies (e.g., corticosteroids, antimalarials, NSAIAs, and/or immunosuppressive agents [e.g., azathioprine, methotrexate, mycophenolate]).1 15 Not studied and not recommended in combination with other biologics or IV cyclophosphamide.1 3 4

Belimumab Dosage and Administration

General

  • Consider premedication (e.g., antihistamine) before each infusion to minimize risk of infusion and hypersensitivity reactions.1 13

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Do not infuse concomitantly in the same IV line with other agents.1

Belimumab lyophilized powder must be reconstituted and diluted prior to IV administration.1 Complete infusion within 8 hours of reconstitution.1

Reconstitution

Allow vial to stand at room temperature for 10–15 minutes before reconstitution.1

Add 1.5 or 4.8 mL of sterile water for injection to a vial containing 120 or 400 mg of belimumab powder, respectively, to provide a solution containing 80 mg/mL.1 Direct sterile water diluent toward side of vial to minimize foaming.1 Gently swirl vial for 60 seconds every 5 minutes until the powder is dissolved; do not shake.1

Dissolution usually occurs within 10–15 minutes but may require up to 30 minutes.1

Protect the reconstituted solution from direct sunlight.1

Dilution

Dilute reconstituted solution with 0.9% sodium chloride injection to a final volume of 250 mL.1

Prior to adding the reconstituted solution to the infusion bag or bottle, withdraw and discard a volume of 0.9% sodium chloride injection equal to the volume of reconstituted solution to be added.1 Add the total required volume of reconstituted belimumab to the diluent. Gently invert the infusion bag or bottle to mix thoroughly; do not shake.1

Rate of Administration

Infuse over 1 hour.1

If an infusion reaction occurs, slow or interrupt the infusion.1 If a serious hypersensitivity reaction occurs, stop the infusion immediately.1

Dosage

Adults

Systemic Lupus Erythematosus
IV

10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.1

Special Populations

Hepatic Impairment

No specific dosage recommendations.1

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

No specific dosage recommendations; use with caution.1

Cautions for Belimumab

Contraindications

  • Known history of anaphylaxis to belimumab.1

Warnings/Precautions

Mortality

More deaths were reported with belimumab than with placebo in clinical studies in SLE.1 Etiologies included infection, cardiovascular disease, and suicide; however, no single cause of death predominated.1

Infectious Complications

Serious, sometimes fatal infections (e.g., bronchitis, pneumonia, urinary tract infection, cellulitis) reported.1

Use caution when considering belimumab in patients with chronic infections.1 Do not begin therapy with belimumab in patients receiving any therapy for chronic infection.1

If a new infection develops, consider interrupting belimumab therapy and monitor the patient closely.1

Malignancy

Immunosuppressive therapy may increase risk of malignancies.1 Effect of belimumab on the development of malignancies is unknown.1 Malignancies were reported during clinical trials. 1

Sensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, hypotension, angioedema, urticaria or other rash, pruritus, dyspnea) reported in 13% of patients.1 Not possible in all cases to distinguish between hypersensitivity and infusion reactions.1

Insufficient experience to establish whether premedication regimens reduce the frequency or severity of hypersensitivity reactions.1

Administer by healthcare providers prepared to manage anaphylaxis.1 If a serious hypersensitivity reaction occurs, immediately discontinue infusion and provide appropriate supportive care.1 Monitor during and for an appropriate period of time after administration.1

Infusion Reactions

Infusion reactions (e.g., headache, nausea, skin reactions) reported in 17% of patients.1 Serious reactions have included bradycardia, myalgia, headache, rash, urticaria, and hypotension.1

Insufficient experience to establish whether premedication regimens reduce the frequency or severity of infusion reactions.1

Administer by healthcare providers prepared to manage infusion reactions.1 If an infusion reaction occurs, interrupt or slow the infusion.1

Psychiatric Effects

Psychiatric events (e.g., depression, insomnia, anxiety) reported.1 Most patients reporting serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive drugs.1 Unknown if belimumab increases risk for these events.1

Immunization

Avoid live vaccines.1 (See Vaccines under Interactions.)

Concomitant Therapy

Not studied in combination with other biologic therapies, including B-cell-targeted therapies, or IV cyclophosphamide; use not recommended in combination with these therapies.1

Immunogenicity

Antibodies to belimumab, including neutralizing antibodies, detected.1 Mild infusion-related reactions reported in several patients with antibody formation; however, clinical importance of antibelimumab antibodies is unknown.1

Specific Populations

Pregnancy

Category C.1 Women of childbearing potential should use effective contraceptive method during treatment and for ≥4 months after discontinuance of the drug.1

Benlysta pregnancy registry (for clinicians and patients) at 877-681-6296.1

Lactation

Distributed into milk in cynomolgus monkeys; not known whether distributed into human milk or absorbed systemically following ingestion.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; use with caution.1

Hepatic Impairment

No formal studies of effects of hepatic impairment on pharmacokinetics.1 Not studied in patients with severe hepatic impairment.1

Renal Impairment

Studied in a limited number of patients with moderate to severe renal impairment.1

Blacks

Limited experience in black patients with SLE.1 11 13 Response in phase 2 study did not appear to vary by race; however, exploratory analysis of phase 3 data indicated response rates were lower for blacks receiving belimumab than for blacks receiving placebo.1 No definitive conclusions can be drawn; use caution when considering belimumab for treatment of SLE in black patients.1

Common Adverse Effects

Nausea,1 3 diarrhea,1 3 pyrexia,1 nasopharyngitis,1 bronchitis,1 insomnia,1 pain in extremity,1 depression,1 migraine,1 3 pharyngitis.1

Interactions for Belimumab

No formal drug interaction studies to date.1

Vaccines

No data available on effects of immunization in patients receiving belimumab.1 Belimumab may interfere with immune response to vaccines.1

Avoid live vaccines during and within 30 days prior to initiation of belimumab therapy; safety not established.1 No data available on secondary transmission of infection by live vaccines in belimumab-treated patients.1

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Increased systemic clearance of belimumab1

Not considered clinically important1

Antimalarials (e.g., chloroquine, hydroxychloroquine)

No substantial effect on belimumab pharmacokinetics1 14 15

Corticosteroids

Increased systemic clearance of belimumab1

Not considered clinically important1

HMG-CoA reductase inhibitors (statins)

No substantial effect on belimumab pharmacokinetics1

Immunomodulatory and immunosuppressive agents

Possible increased risk of infection13

Azathioprine, methotrexate, mycophenolate: No substantial effect on belimumab pharmacokinetics1

Concomitant use of other biologic agents (e.g., B-cell-targeted therapies) or IV cyclophosphamide not recommended1

NSAIAs (including aspirin)

No substantial effect on belimumab pharmacokinetics1

Belimumab Pharmacokinetics

Elimination

Half-life

19.4 days.1

Special Populations

Hepatic impairment: Pharmacokinetics not formally studied.1 In population pharmacokinetic analyses, baseline transaminase (AST, ALT) or bilirubin concentration did not explain variability in drug clearance.1 14 However, not studied in severe hepatic impairment.1

Renal impairment: Pharmacokinetics not formally studied.1 In population pharmacokinetic analyses, drug clearance was increased at higher Clcr rates and with proteinuria >2 g daily, but effects are unlikely to be clinically important.1 14

Stability

Storage

Parenteral

Powder for Injection

2–8°C.1 Protect from light; do not freeze.1

If reconstituted solution is not used immediately, store at 2–8°C and protect from direct sunlight.1 Store diluted solution at 2–8°C or room temperature.1 Total time from reconstitution to completion of infusion should not exceed 8 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%1

Incompatible

Dextrose solutions1

Actions

  • Inhibits biologic effects of soluble BLyS.1 3 4 5 6 BLyS inhibits B-cell apoptosis and stimulates differentiation of B cells into immunoglobulin-producing plasma cells.4

  • Inhibits binding of soluble BLyS to its receptors on B cells, thereby inhibiting B-cell (including autoreactive B-cell) survival and reducing differentiation of B cells into immunoglobulin-producing plasma cells.1 6

  • Treatment reduces circulating CD19+, CD20+, naive, and activated B cells, plasmacytoid cells, and the SLE B-cell subset, as well as IgG and antibodies to double-stranded DNA (anti-dsDNA).1 Memory cells increase initially and slowly decline toward baseline.1 Complement (C3 and C4) levels are increased.1 Clinical relevance of these effects not definitively established.1

Advice to Patients

  • Importance of the patient reading the medication guide before initiating therapy and before each subsequent infusion.1 2

  • Importance of informing patients that there were more deaths among belimumab-treated patients than among placebo recipients during clinical trials in patients with SLE.1

  • Risk of increased susceptibility to infection.1 Importance of promptly informing clinicians if any signs or symptoms of infection (e.g., fever, chills, pain or burning on urination, frequent urination, bloody diarrhea, cough) develop.1 2

  • Risk of hypersensitivity reactions, including anaphylaxis.1 2 Importance of seeking immediate medical care if signs or symptoms of hypersensitivity reactions (e.g., wheezing, difficulty breathing, perioral or lingual edema, rash) occur.1 2

  • Importance of promptly reporting new or worsening depression, suicidal thoughts, or other mood changes.1 2

  • Importance of not receiving live vaccines during belimumab therapy.1 2

  • Importance of promptly reporting symptoms of cardiac disease (e.g., chest discomfort or pain, shortness of breath, cold sweats, nausea, dizziness).2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 Advise women of childbearing potential to use effective contraceptive method during treatment and for ≥4 months following discontinuance of the drug.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or dietary supplements, as well as any concomitant illnesses or history of chronic infections.1 2

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Belimumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

120 mg

Benlysta

Human Genome Services, (also promoted by GlaxoSmithKline)

400 mg

Benlysta

Human Genome Services, (also promoted by GlaxoSmithKline)

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Human Genome Sciences. Benlysta (belimumab) for injection prescribing information. Rockville, MD; 2011 Mar.

2. Human Genome Sciences. Benlysta (belimumab) for injection patient information. Rockville, MD; 2011 Mar.

3. Navarra SV, Guzmán RM, Gallacher AE et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, phase 3 trial. Lancet. 2011; 377:721-31. [PubMed 21296403]

4. Wallace DJ, Stohl W, Furie RA et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009; 61:1168-78. [PubMed 19714604]

5. Furie R, Stohl W, Ginzler EM et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther. 2008; 10:R109. [PubMed 18786258]

6. Baker KP, Edwards BM, Main SH et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 2003; 48:3253-65. [PubMed 14613291]

7. van Vollenhoven RF, Zamani O, Wallace DJ, et al. Belimumab, a BLyS-specific inhibitor reduces disease activity and severe flares in seropositive. Ann Rheum Dis. 2010; 69:74.

8. Petri M, Furie R, Merril J, et al. Four-year experience of belimumab, a BLyS specific inhibitor, in systemic lupus erythematosus (SLE) patients. Arthritis Rheum. 2009; 60:Abstract No. 2069.

9. Jacobi AM, Huang W, Wang T et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2010; 62:201-10. [PubMed 20039404]

10. Furie RA, Petri MA, Wallace DJ et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009; 61:1143-51. [PubMed 19714615]

11. Mitka M. Treatment for lupus, first in 50 years, offers modest benefits, hope to patients. JAMA. 2011; 305:1754-5. [PubMed 21540415]

12. Stone JH. BLISS! Lupus learns its lessons. Lancet. 2011; 377:693-4. [PubMed 21296404]

13. . Belimumab (Benlysta) for systemic lupus erythematosus. Med Lett Drugs Ther. 2011; 53:45-6. [PubMed 21659968]

14. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125370 (belimumab): Clinical pharmacology and biopharmaceutics review(s). From FDA website.

15. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125370 (belimumab): Medical review(s). From FDA website.

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