What are the side effects of Nivolumab (Opdivo)?

Nivolumab Side Effects: Recognition and Management

Nivolumab commonly causes immune-related adverse events (irAEs) that can affect virtually any organ system, with the most frequent being cutaneous toxicities, gastrointestinal toxicities, and fatigue, while less common but potentially life-threatening toxicities include pneumonitis, hepatitis, and myocarditis. 1, 2

Common Side Effects

Nivolumab's side effect profile differs significantly from conventional chemotherapy, with most toxicities being autoimmune in nature:

Most Common Side Effects

• Skin toxicities (median onset 5 weeks):

  • Rash (20-30% of patients)
  • Pruritus (itching)
  • Maculopapular rash
  • Vitiligo 1, 2

• Gastrointestinal toxicities (median onset 7.3 weeks):

  • Diarrhea (10-20% of patients)
  • Colitis
  • Nausea
  • Vomiting 1

• General symptoms:

  • Fatigue (very common)
  • Decreased appetite
  • Fever 1, 3

Timing of Toxicities

• Early toxicities (median onset <2 months):

  • Skin (5 weeks)
  • Gastrointestinal (7.3 weeks)
  • Hepatic (7.7 weeks) 2

• Late toxicities (median onset >2 months):

  • Pulmonary (8.9 weeks)
  • Endocrine (10.4 weeks)
  • Renal (15.1 weeks) 2

Serious Immune-Related Adverse Events

Endocrinopathies

• Hypothyroidism and hyperthyroidism
• Hypophysitis (pituitary inflammation)
• Adrenal insufficiency (including isolated ACTH deficiency)
• Type 1 diabetes mellitus 1, 4, 5

Hepatic Toxicity

• Elevated ALT/AST (10-11% with combination therapy)
• Hepatitis 1, 2

Pulmonary Toxicity

• Pneumonitis (3-7% of patients) - potentially life-threatening
• Dyspnea
• Cough 1

Neurological Toxicity

• Polyneuropathy
• Facial nerve palsy
• Guillain-Barré syndrome
• Myasthenia gravis
• Encephalitis
• Aseptic meningitis 1

Cardiac Toxicity

• Myocarditis
• Pericarditis
• Arrhythmias
• Cardiomyopathy 1

Other Rare but Serious Toxicities

• Renal toxicity (nephritis)
• Ocular toxicities (uveitis, scleritis)
• Hematological toxicities (aplastic anemia, autoimmune hemolytic anemia)
• Severe infusion reactions 1, 6, 7

Management Approach

General Principles

1. Grade-based management:

   • Grade 1 (mild): Continue nivolumab with close monitoring
   • Grade 2 (moderate): Hold nivolumab, initiate oral corticosteroids (0.5-1 mg/kg/day prednisone)
   • Grade 3-4 (severe): Permanently discontinue nivolumab, high-dose corticosteroids (1-2 mg/kg/day prednisone) 2

2. Specialist consultation:

   • Early consultation with appropriate specialists based on affected organ system
   • Endocrinology for endocrinopathies
   • Gastroenterology for colitis
   • Pulmonology for pneumonitis
   • Cardiology for cardiac toxicities 1, 2

Specific Management Strategies

Skin Toxicities

• Grade 1-2: Topical corticosteroids, oral antihistamines
• Grade 3-4: Systemic corticosteroids 2

Gastrointestinal Toxicities

• Grade 2: Hold therapy, oral corticosteroids
• Grade 3-4: Permanently discontinue nivolumab, high-dose steroids
• Steroid-refractory cases: Consider infliximab 1, 2, 8

Endocrinopathies

• Often require hormone replacement rather than immunosuppression
• Thyroid dysfunction: Thyroid hormone replacement for hypothyroidism
• Adrenal insufficiency: Hydrocortisone replacement
• Hypophysitis: Hormone replacement based on deficiencies 2, 4, 5

Pneumonitis

• Grade 2: Hold therapy, initiate corticosteroids
• Grade 3-4: Permanently discontinue nivolumab, high-dose steroids
• If no improvement after 2 days, consider additional immunosuppressants 1, 2

Hepatitis

• Monitor liver function tests regularly
• Grade 2: Hold therapy, initiate corticosteroids
• Grade 3-4: Permanently discontinue nivolumab, high-dose steroids 2

Special Considerations

Combination Therapy

• Nivolumab + ipilimumab has higher toxicity rates (54-59% grade 3-4 toxicities) compared to nivolumab monotherapy (22% grade 3-4 toxicities) 1
• More aggressive monitoring and earlier intervention may be needed with combination therapy 2

Post-Treatment Monitoring

• Toxicities can develop even after therapy cessation
• Monitor every 3 months during the first year, then every 6 months
• Include laboratory tests: CBC, renal function, electrolytes, glycemia, liver function, and TSH 2

Common Pitfalls to Avoid

• Delayed recognition of immune-related toxicities can be potentially fatal
• Inadequate steroid duration/tapering can lead to recurrence of toxicity
• Insufficient monitoring after treatment can lead to delayed recognition of irAEs
• Misdiagnosis of general symptoms (fatigue, malaise) as disease progression rather than treatment toxicity 2, 4