What are the potential side effects and usage considerations for Enbrel (etanercept) in adults and children, especially those with a history of infections or immunocompromised status?

Enbrel (Etanercept) Side Effects

Enbrel carries a black box warning for serious infections (including tuberculosis reactivation) and malignancies, particularly in children and adolescents, and should be discontinued immediately if serious infection or sepsis develops. 1

Most Common Side Effects

• Injection site reactions occur in 14-67.7% of patients, representing the most frequent adverse effect 2, 3
• These reactions are typically mild to moderate, diminish with ongoing therapy, and do not correlate with antibody development 3, 2
• Upper respiratory tract infections are commonly reported 3, 4
• Headache occurs frequently 3, 5
• Other common effects include rhinitis and dizziness 5, 4

Serious Infections (Black Box Warning)

Tuberculosis Reactivation

• Latent TB reactivation is a major concern, with approximately 50% of cases presenting as extrapulmonary or disseminated disease 3, 2, 1
• Etanercept carries a lower TB risk compared to monoclonal TNF antagonists (infliximab: 103 per 100,000 patient-years; adalimumab: 171 per 100,000 patient-years; etanercept: 39 per 100,000 patient-years) 3
• Median time to TB diagnosis is 11.5 months after starting etanercept (versus 3 months for infliximab and 4-6 months for adalimumab) 3
• Mandatory screening: Tuberculin skin testing (≥5 mm induration is positive) and chest radiograph must be performed before initiating therapy 3, 2, 1
• Patients testing negative for latent TB before therapy can still develop tuberculosis during treatment 1

Other Serious Infections

• Invasive fungal infections including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis may present as disseminated disease 1
• Bacterial, viral, and opportunistic infections including Legionella and Listeria 1
• Soft tissue infections, sepsis, pneumonia, bronchitis, peritonitis, cellulitis, and herpes zoster 3
• Hepatitis B reactivation occurs in patients with chronic HBV infection or chronic carriers 3, 2

Malignancy Risk (Black Box Warning)

• Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers 1
• Postmarketing surveillance reports non-Hodgkin's lymphoma, including cases where lymphoma regressed after drug cessation 2
• The largest rheumatoid arthritis study did not demonstrate statistically significant increased lymphoma incidence 2
• Increased risk of skin cancer: non-melanoma skin cancer relative risk 1.7 (95% CI 1.3-2.2) and melanoma 2.6 (95% CI 1.0-6.7) 3

Autoimmune and Inflammatory Complications

• Lupus-like syndrome has been reported 3, 2
• Antinuclear antibodies develop in up to 11% of patients, though they rarely lead to overt autoimmune disease during short- to medium-duration use 2
• Vasculitis has been reported in patients on anti-TNF therapy 3

Neurological Complications

• CNS demyelination including optic neuritis, transverse myelitis, and Guillain-Barré syndrome have been observed in postmarketing reports 2
• Etanercept is contraindicated in patients with active demyelinating diseases 2
• Rare reports of seizures and peripheral neuropathy 3

Cardiovascular Effects

• Must be avoided in severe congestive heart failure (NYHA class III or IV) 2
• Etanercept has not been convincingly linked to the increased mortality seen with infliximab in heart failure patients 2

Hematologic Toxicities

• Blood dyscrasias including anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and hemophagocytic syndrome 2
• Cytopenias have been reported in clinical trials 3

Hepatotoxicity

• Elevation in liver transaminases occurs, generally transient and asymptomatic 3
• Rare cases of severe hepatitis and acute liver failure resulting in transplantation or death have been reported 3

Other Adverse Effects

• Diabetic ketoacidosis, hyperthyroidism, and thyroiditis 2
• Pulmonary fibrosis as either new event or exacerbation of underlying fibrosis 3
• Sarcoidosis has been reported with anti-TNF agents 3
• Gastrointestinal disturbances 5

Critical Monitoring Requirements

Before Starting Therapy:

• Tuberculin skin testing (PPD ≥5 mm is positive) and chest radiograph are mandatory 3, 2, 1
• Hepatitis B serology must be obtained 3
• Consider risk for histoplasmosis, blastomycosis, or coccidioidomycosis in endemic areas 3
• Comprehensive dermatological assessment for skin cancer, especially in patients with prior PUVA (>200 treatments) or UVB (>350 treatments) therapy 3

During Therapy:

• Patients must immediately report fever, cough, aches, chills, wounds with redness/pain/discharge, burning with urination, or gastrointestinal symptoms 3
• Monitor for viral hepatitis reactivation in patients with history of viral hepatitis or chronic carrier states 3
• Regular dermatological assessment for skin cancer at 3-6 month intervals 3
• Clinical awareness for TB should be maintained throughout therapy and for 6 months after cessation 3

Contraindications and Special Populations

Absolute Contraindications:

• Active serious infections or sepsis 1
• Active demyelinating diseases 2
• Severe congestive heart failure (NYHA class III or IV) 2

Pregnancy and Breastfeeding:

• FDA pregnancy category B for all trimesters 3, 2
• Insufficient clinical data exist to confirm safety in breastfeeding 2
• No adequate, well-controlled studies in pregnant women 3

Drug Interactions:

• Live vaccines must be avoided during etanercept therapy 3, 2
• Concomitant immunosuppressants (methotrexate, corticosteroids) increase infection risk 1

Relative Contraindications

• Biologic therapy should be avoided in patients with current or recent malignancy unless diagnosed and treated >5 years previously or where likelihood of cure is high 3
• Prior therapy with >200 PUVA and/or >350 UVB treatments, especially when followed by ciclosporin 3
• Chronic or recurrent infections 1, 4