Etanercept - Drug Monograph

Introduction

Etanercept is a biologic disease-modifying antirheumatic drug (DMARD) that functions as a tumor necrosis factor (TNF) inhibitor. It is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human immunoglobulin G1 (IgG1). First approved by the FDA in 1998, etanercept has revolutionized the treatment of several autoimmune and inflammatory conditions by specifically targeting the inflammatory cascade.

Mechanism of Action

Etanercept works by competitively inhibiting the binding of tumor necrosis factor-alpha (TNF-α) and TNF-β (lymphotoxin-alpha) to their cell surface receptors. TNF-α is a proinflammatory cytokine that plays a pivotal role in the inflammatory processes of various autoimmune diseases. By binding to soluble and membrane-bound TNF, etanercept prevents TNF from interacting with its receptors, thereby reducing the inflammatory response. The drug does not lyse cells expressing TNF in vitro, distinguishing it from some other TNF inhibitors.

Indications

FDA-approved indications for etanercept include:

• Moderate to severe rheumatoid arthritis (as monotherapy or in combination with methotrexate)
• Psoriatic arthritis
• Ankylosing spondylitis
• Moderate to severe plaque psoriasis in adults
• Moderate to severe polyarticular juvenile idiopathic arthritis in patients aged 2 years and older
• Non-radiographic axial spondyloarthritis with objective signs of inflammation

Dosage and Administration

• Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis: 50 mg subcutaneous injection once weekly
• Plaque psoriasis: 50 mg subcutaneous injection twice weekly for 3 months, then reduced to 50 mg once weekly
• Juvenile idiopathic arthritis: Based on weight (0.8 mg/kg per week, maximum 50 mg per week)

• Administered as subcutaneous injection
• Rotate injection sites (thigh, abdomen, upper arm)
• Allow refrigerated solution to reach room temperature (approximately 15-30 minutes) before injection
• Do not shake the solution

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: No specific recommendations
• Elderly: No dosage adjustment necessary, but increased infection risk
• Pregnancy: Category B - use only if clearly needed

Pharmacokinetics

Contraindications

• Hypersensitivity to etanercept or any component of the formulation
• Sepsis or risk of sepsis
• Active infections, including chronic or localized infections
• Live vaccines should not be administered concurrently

Warnings and Precautions

• Serious infections leading to hospitalization or death, including tuberculosis, bacterial sepsis, invasive fungal infections, and opportunistic infections
• Increased risk of lymphoma and other malignancies, particularly in children and adolescents

• Hepatitis B virus reactivation
• Neurologic events (exacerbation or new onset demyelinating disease)
• Hematologic events (pancytopenia, aplastic anemia)
• Heart failure (worsening or new onset)
• Hypersensitivity reactions
• Autoimmunity (development of autoantibodies/lupus-like syndrome)

Drug Interactions

• Live vaccines: Contraindicated (increased risk of infection)
• Anakinra: Increased risk of serious infections (not recommended)
• Abatacept: Increased risk of serious infections (not recommended)
• Other TNF blockers: Increased risk of adverse effects (not recommended)
• Cyclophosphamide: Not recommended due to increased infection risk
• Theophylline: May decrease theophylline concentrations (monitor levels)

Adverse Effects

• Injection site reactions (erythema, itching, pain, swelling)
• Upper respiratory tract infections
• Headache

• Infections (including serious infections)
• Rash
• Dizziness
• Abdominal pain
• Elevated liver enzymes
• Autoantibody formation

• Serious infections (sepsis, tuberculosis, opportunistic infections)
• Malignancies (lymphoma, other cancers)
• Demyelinating disorders
• Congestive heart failure exacerbation
• Hematologic disorders (pancytopenia, aplastic anemia)
• Severe hypersensitivity reactions
• Hepatitis B reactivation

Monitoring Parameters

• Tuberculosis screening (PPD or IGRA testing)
• Hepatitis B and C serology
• Complete blood count with differential
• Liver function tests
• Renal function tests
• Pregnancy test if appropriate

• Signs and symptoms of infection at every visit
• CBC, LFTs every 3-6 months
• Periodic skin examination (psoriasis patients)
• Monitor for signs of malignancy
• Assess for neurologic symptoms
• Evaluate for signs of heart failure
• Monitor for autoimmune symptoms

• Rheumatoid arthritis: Disease activity scores, functional assessment
• Psoriasis: PASI scores, body surface area assessment
• Inflammatory arthritis: Joint counts, mobility assessment

Patient Education

• Instruct on proper injection technique and site rotation
• Recognize and report signs of infection (fever, cough, flu-like symptoms)
• Avoid live vaccines during treatment
• Report any new neurological symptoms (numbness, tingling, vision changes)
• Monitor for signs of malignancy (unexplained weight loss, night sweats)
• Inform all healthcare providers about etanercept use
• Do not stop other medications unless directed by physician
• Report any skin reactions or unusual bruising/bleeding
• Discuss pregnancy plans with healthcare provider before conception
• Store medication properly (refrigerate, do not freeze)
• Dispose of needles and syringes in puncture-proof container

References

1. Singh JA, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(1):1-26. 2. Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2019;80(4):1029-1072. 3. Enbrel® (etanercept) prescribing information. Amgen Inc.; 2021. 4. Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-699. 5. FDA Drug Safety Communication: Boxed Warning updated for increased risk of lymphoma and other malignancies. FDA.gov. 2021. 6. Winthrop KL, et al. Tuberculosis and other opportunistic infections in patients receiving anti-TNF therapy. Clin Infect Dis. 2021;72(9):e795-e803. 7. Gelfand JM, et al. Comparative effectiveness of biologic and conventional systemic therapies in adults with psoriasis. JAMA Dermatol. 2020;156(3):258-269.