What are the indications and contraindications for Pirfenidone (Pirfenidone) and Nintedanib (Nintedanib) in Interstitial Lung Disease (ILD)?

Indications and Contraindications for Pirfenidone and Nintedanib in Interstitial Lung Disease (ILD)

Nintedanib is recommended for progressive pulmonary fibrosis (PPF) in patients who have failed standard management for fibrotic ILD other than idiopathic pulmonary fibrosis (IPF), while pirfenidone has more limited indications primarily in IPF and possibly RA-ILD progression. 1

Nintedanib Indications

Primary Indications:

• Idiopathic pulmonary fibrosis (IPF) - first-line therapy 1
• Progressive pulmonary fibrosis (PPF) in patients who have failed standard management for fibrotic ILD other than IPF 1
• Systemic sclerosis-associated ILD (SSc-ILD) progression despite first-line treatment 1
• Chronic fibrosing ILD with progressive phenotype 2

Secondary Indications (Based on Disease Progression):

• For SARD-ILD (systemic autoimmune rheumatic disease-associated ILD) progression despite first ILD treatment 1
• For RA-ILD (rheumatoid arthritis-associated ILD), no consensus was reached on first-line use, but recommended for progression 1

Contraindications for Nintedanib:

• Severe hepatic or renal impairment 3
• Concurrent fluvoxamine use 3
• Smoking (relative contraindication) 3
• First-line therapy for SjD-ILD (Sjögren's disease), IIM-ILD (idiopathic inflammatory myopathy), and MCTD-ILD (mixed connective tissue disease) 1
• Rapidly progressive ILD (RP-ILD) in SARD patients 1

Pirfenidone Indications

Primary Indications:

• Idiopathic pulmonary fibrosis (IPF) - first-line therapy 3
• RA-ILD progression despite first ILD treatment 1

Contraindications for Pirfenidone:

• First-line therapy for SARD-ILD 1
• SARD-ILD other than RA-ILD progression 1
• Rapidly progressive ILD (RP-ILD) in SARD patients 1

Dosing and Monitoring

Nintedanib:

• Dosage: 150 mg twice daily 1
• Monitoring:
  • Monthly liver function tests for first 6 months, then every 3 months 3
  • Regular assessment of FVC decline 1

Pirfenidone:

• Dosage: Titrated to 801 mg three times daily 4
• Monitoring:
  • Regular liver function tests 3
  • Clinical assessment for adverse effects 3

Adverse Effects

Nintedanib:

• Gastrointestinal adverse events (most common) 1:
  • Diarrhea (2.8× increased risk)
  • Nausea (3.1× increased risk)
  • Vomiting (3.6× increased risk)
  • Abdominal pain (4.2× increased risk)
  • Anorexia (2.8× increased risk)
  • Weight loss (3.7× increased risk)
• Hepatic effects:
  • Elevated AST (3.2× increased risk)
  • Elevated ALT (3.6× increased risk)
• Higher likelihood of dose reduction (7.9× increased risk) 1
• Treatment discontinuation (1.9× increased risk) 1

Pirfenidone:

• Gastrointestinal symptoms 5, 6
• Photosensitivity and skin rashes 5
• Higher discontinuation rate (40%) compared to nintedanib (16.3%) in real-world studies 6

Clinical Decision Algorithm

1. For IPF patients:

   • Either nintedanib or pirfenidone as first-line therapy
   • Base selection on comorbidities and potential side effect profile
   • Consider baseline liver function and skin sensitivity

2. For non-IPF ILD with progressive fibrosis:

   • Nintedanib after failure of standard management
   • Standard management varies by ILD type (may include immunosuppression, antigen remediation, or observation)

3. For SARD-ILD:

   • First-line: Standard management based on underlying disease
   • For progression despite first-line therapy:
     • SSc-ILD: Consider nintedanib
     • RA-ILD: Consider either nintedanib or pirfenidone
     • Other SARD-ILD: Consider nintedanib but not pirfenidone

4. For rapidly progressive ILD:

   • Neither nintedanib nor pirfenidone recommended as first-line
   • Consider pulse methylprednisolone, rituximab, cyclophosphamide, IVIG, mycophenolate, CNI, or JAK inhibitors 1

Important Caveats

• Patients with baseline FVC <65% predicted may have shorter duration of pirfenidone therapy before discontinuation due to adverse events 6
• Neither drug stops disease progression completely; they only slow the rate of decline 1, 5
• Combination therapy (nintedanib + pirfenidone) has been studied with manageable safety profile but is not standard practice 4
• For SARD-ILD receiving mycophenolate without evidence of progression, adding nintedanib or pirfenidone is not recommended 1
• Both medications require close monitoring for adverse effects, particularly gastrointestinal and hepatic 1, 3

Efficacy Considerations

• Nintedanib reduces annual FVC decline by approximately 107 ml compared to placebo in PPF 1
• The difference in FVC decline is more pronounced in patients with UIP pattern (128 ml/yr) compared to non-UIP pattern (75.3 ml/yr) 1
• Pirfenidone efficacy in non-IPF ILD should be interpreted with caution due to trial limitations 7

The decision to initiate antifibrotic therapy should be made after careful consideration of disease progression, underlying ILD type, potential adverse effects, and patient preferences, with regular monitoring of both efficacy and tolerability.