What medications are contraindicated in patients with Interstitial Lung Disease (ILD)?

Medications Contraindicated in Interstitial Lung Disease

Ambrisentan is absolutely contraindicated in idiopathic pulmonary fibrosis (IPF), including IPF with severe pulmonary hypertension, due to demonstrated detrimental effects on mortality and increased hospitalizations for respiratory complications. 1

Formally Contraindicated Medications

Endothelin Receptor Antagonists

• Ambrisentan is the only medication with a formal contraindication in IPF 1, 2
  • The ARTEMIS-IPF trial showed detrimental effects on time to death or worsening of pulmonary function 1
  • Associated with increased rate of hospitalizations for respiratory complications 1
  • This contraindication extends to IPF patients with severe pulmonary hypertension 1

Medications Not Recommended (Strong Evidence Against Use)

Anticoagulants for IPF Treatment

• Warfarin and other oral anti-vitamin K anticoagulants should not be prescribed to treat IPF 1, 2
  • A randomized trial was prematurely discontinued due to increased mortality (p<0.005) in the warfarin group 1
  • Increased prevalence of adverse events without survival benefit 1
  • Important caveat: These agents are not contraindicated if indicated for other reasons (e.g., cardiovascular indications) 1

Immunosuppressive Agents in IPF

• Triple therapy with prednisone, azathioprine, and N-acetylcysteine is strongly contraindicated in IPF due to increased mortality 2
• Corticosteroid therapy (with or without immunomodulators) should not be used in definite IPF except for acute exacerbations 1, 2
  • No survival benefit demonstrated in controlled trials 1
  • Associated with substantial long-term morbidity 1
  • Exception: Low-dose prednisone (≤10 mg/day) may be used for incapacitating cough 1
  • Exception: High-dose corticosteroids for acute exacerbations 1

Other Ineffective/Harmful Agents in IPF

• Colchicine: No clinical efficacy demonstrated in multiple trials 1
• Cyclosporine A: Disease progression observed even with use 1
• Interferon-γ-1b: No effect on disease progression or survival 1
• Etanercept: No improvement in primary endpoints 1
• Bosentan and macitentan: No improvement in disease progression or quality of life 1

Medications That Can Cause Drug-Induced ILD

High-Risk Medications Requiring Vigilance

Clinicians must be aware that the following medications used to treat connective tissue diseases can paradoxically cause drug-induced ILD 1:

• TNF-alpha inhibitors 1
• Methotrexate 1
• Leflunomide 1
• Rituximab (can cause pneumonitis and worsening of ILD) 1
• Cyclophosphamide 1
• Sulfasalazine 1
• Sulfonamides 1

Management of Drug-Induced ILD

• Requires bronchoscopy, biopsy, and/or withdrawal of the medication 1
• Corticosteroids may be used if significant symptoms and respiratory impairment are present 1
• While the risk is low for most agents (approximately 1%), vigilance is essential 1

Context-Specific Considerations

IPF vs. Autoimmune-Associated ILD

The contraindications differ significantly based on ILD etiology:

• For IPF: Immunosuppression is contraindicated; antifibrotics (nintedanib, pirfenidone) are first-line 2, 3
• For Sjögren's-ILD and other CTD-ILD: Immunomodulatory therapy (rituximab, cyclophosphamide, mycophenolate) may be appropriate 1, 3
• For rapidly progressive autoimmune ILD: High-dose IV corticosteroids are recommended, contrary to IPF management 1, 4

Critical Pitfall to Avoid

Do not extrapolate IPF treatment contraindications to all forms of ILD. 1 Autoimmune-associated ILD may benefit from immunosuppression that would be harmful in IPF. Always confirm the specific ILD subtype before determining contraindications 1, 3

Special Warnings with Antifibrotic Therapy

While nintedanib and pirfenidone are first-line for IPF, they themselves can paradoxically cause drug-induced ILD 5:

• Both drugs showed signals for ILD development in adverse event databases 5
• Monitor closely for worsening respiratory symptoms that may indicate drug-induced injury rather than disease progression 5