Benlysta - Drug Monograph

Introduction

Benlysta (belimumab) is a first-in-class biologic therapy approved for the treatment of systemic lupus erythematosus (SLE). It represents a significant advancement in lupus treatment as the first drug specifically developed for SLE in over 50 years. Benlysta is a human monoclonal antibody that targets B-lymphocyte stimulator (BLyS), playing a crucial role in modulating the abnormal B-cell activity characteristic of lupus.

Mechanism of Action

Benlysta exerts its therapeutic effect through targeted inhibition of B-cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS). This soluble protein is essential for the survival, differentiation, and maturation of B lymphocytes into plasma cells that produce autoantibodies. By binding to soluble BLyS, Benlysta prevents its interaction with receptors on B cells (BAFF-R, BCMA, and TACI), thereby:

• Reducing the survival of autoreactive B cells
• Decreasing differentiation into autoantibody-producing plasma cells
• Modulating B-cell mediated immune responses without causing broad immunosuppression

This targeted mechanism specifically addresses the pathophysiology of SLE while preserving protective immune functions.

Indications

• Treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard therapy
• Treatment of pediatric patients (5 years and older) with active, autoantibody-positive SLE who are receiving standard therapy

• Typically reserved for patients with inadequate response to conventional therapies including antimalarials, corticosteroids, and immunosuppressants
• Not indicated for severe active lupus nephritis or severe active central nervous system lupus
• May be considered for lupus patients with persistent disease activity despite optimal standard care

Dosage and Administration

• Intravenous: 10 mg/kg every 2 weeks for the first 3 doses, then every 4 weeks thereafter
• Subcutaneous: 200 mg once weekly (after receiving initial IV loading doses or as initial therapy)

• Based on body weight categories:

- <35 kg: IV dose of 10 mg/kg or SC dose of 120 mg weekly - ≥35 kg: IV dose of 10 mg/kg or SC dose of 200 mg weekly

• IV infusion should be administered over 1 hour
• Pre-medication with antihistamines may be considered for prophylaxis against infusion reactions
• SC injection sites should be rotated between abdomen, thighs, or upper arms
• Do not administer SC formulation to patients with known hypersensitivity to rubber or latex

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: No specific recommendations; use with caution
• Geriatric: No dosage adjustment required
• Pregnancy: Category C; use only if potential benefit justifies potential risk

Pharmacokinetics

• IV: Complete bioavailability
• SC: Absolute bioavailability approximately 74%

• Steady-state volume of distribution: ~5.29 L
• Limited tissue distribution due to large molecular size

• Degraded via proteolytic enzymes throughout the body
• No cytochrome P450 enzyme involvement

• Half-life: ~19 days
• Clearance: ~215 mL/day
• Primarily through intracellular catabolism following binding to BLyS

• Approximately 16 weeks with regular dosing

Contraindications

• History of anaphylaxis with belimumab
• Concomitant use with other biologic therapies or IV cyclophosphamide
• Active infection requiring treatment
• Hypersensitivity to any component of the formulation

Warnings and Precautions

• Increased risk of mortality, serious infections, and psychiatric events including depression, suicidal ideation, and behavior

• Increased susceptibility to infections including opportunistic infections
• Consider withholding during acute infections
• Screen for latent tuberculosis before initiation

• Monitor for new or worsening depression, suicidal thoughts, or behavior
• Evaluate risk-benefit in patients with history of psychiatric disorders

• Theoretical increased risk of malignancy with immunosuppressive therapies

• Infusion reactions and anaphylaxis may occur
• Appropriate medical support should be available during infusion

• Live vaccines should not be administered concurrently
• Complete all age-appropriate vaccinations before initiation

• Rare cases reported; monitor for neurological symptoms

Drug Interactions

• Live vaccines: Contraindicated due to theoretical risk of disseminated infection
• Other biologics: Increased risk of immunosuppression and infections
• IV cyclophosphamide: Contraindicated due to lack of safety data

• Immunosuppressants: May enhance immunosuppressive effects
• CYP450 substrates: Unlikely to affect drug metabolism due to non-enzymatic clearance

Adverse Effects

• Nausea (15%)
• Diarrhea (12%)
• Pyrexia (10%)
• Nasopharyngitis (9%)
• Bronchitis (9%)
• Insomnia (7%)
• Leg/arm pain (6%)
• Depression (5%)
• Migraine (5%)
• Leukopenia (5%)

• Serious infections (6%)
• Infusion reactions (0.5%)
• Anaphylaxis (<0.1%)
• Depression with suicidal ideation
• Progressive multifocal leukoencephalopathy

• Leukopenia
• Decreased immunoglobulin levels

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel
• Urinalysis
• Autoantibody profile
• Screening for latent tuberculosis
• Vaccination status review
• Psychiatric assessment

• Clinical response assessment using SLEDAI or other validated tools
• CBC with differential every 4 weeks initially, then every 3 months
• Infection monitoring at every visit
• Psychiatric assessment at each visit
• Immunoglobulin levels periodically

• Vital signs before, during, and after infusion
• Observation for hypersensitivity reactions

Patient Education

• Benlysta is not a cure for lupus but helps control disease activity
• Report any signs of infection immediately (fever, cough, sore throat)
• Seek immediate medical attention for suicidal thoughts or new/worsening depression
• Do not receive live vaccines while taking Benlysta
• Keep all scheduled infusion or injection appointments
• Inform all healthcare providers about Benlysta therapy
• Use reliable contraception during treatment and for 4 months after discontinuation
• Report pregnancy or planning pregnancy to healthcare provider
• Store subcutaneous formulation refrigerated; do not freeze
• Rotate injection sites and avoid areas that are tender, bruised, or scarred

• For SC administration: proper injection technique training required
• For IV administration: plan for approximately 2 hours for entire process

• Signs of infection
• New or worsening depression or mood changes
• Allergic reactions
• Unusual neurological symptoms
• Planned surgery or dental procedures

References

1. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930.

2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731.

3. FDA Prescribing Information: Benlysta (belimumab). Revised 2023.

4. van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343-1349.

5. Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: A fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 2017;69(5):1016-1027.

6. Ginzler EM, Wallace DJ, Merrill JT, et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol. 2014;41(2):300-309.

7. Brunner HI, Abud-Mendoza C, Viola DO, et al. Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial. Ann Rheum Dis. 2020;79(10):1340-1348.