What is the role of Nintedanib (generic name: Nintedanib) in the treatment of patients with idiopathic pulmonary fibrosis (IPF) or other forms of progressive interstitial lung disease (ILD)?

Nintedanib in Interstitial Lung Disease

Nintedanib at 150 mg twice daily is strongly recommended for patients with idiopathic pulmonary fibrosis (IPF) and should be initiated early in the disease course to preserve lung function, and is conditionally recommended for progressive pulmonary fibrosis (PPF) in non-IPF fibrotic ILDs when patients demonstrate disease progression. 1

Mechanism and Core Efficacy

Nintedanib is an intracellular inhibitor targeting multiple tyrosine kinases including VEGF, FGF, and PDGF receptors, which are key drivers of fibrosis. 1, 2

In Idiopathic Pulmonary Fibrosis:

• Reduces annual FVC decline by approximately 125 ml/year compared to placebo (difference 125.2 ml; 95% CI 77.7-172.8), representing meaningful slowing of disease progression 1, 3, 2
• Reduces risk of acute IPF exacerbations (HR 0.38-1.15 depending on trial, with INPULSIS-2 showing HR 0.38; 95% CI 0.19-0.77) 1, 2
• Does not show statistically significant mortality benefit (RR 0.70; 95% CI 0.47-1.03), though trend favors treatment 3
• Reduces proportion of patients experiencing ≥10% absolute FVC decline (RR 1.16; 95% CI 1.06-1.27) 3

In Progressive Pulmonary Fibrosis (Non-IPF):

• Reduces annual FVC decline by approximately 107 ml compared to placebo in patients meeting PPF criteria 1, 4
• Decreases risk of ILD progression 2.4-fold 1, 4
• Efficacy varies by underlying disease: CTD-related ILD (106.2 ml/yr preservation), fibrotic NSIP (141.7 ml/yr), and fibrotic occupational lung disease (252.8 ml/yr) 1, 4

Patient Selection Algorithm

For IPF:

1. Initiate nintedanib 150 mg twice daily in all patients with confirmed IPF diagnosis regardless of disease severity 1
2. Start treatment early in the disease course to maximize lung function preservation 1
3. Efficacy is consistent across age groups (including ≥75 years) and comorbidity burden 5

For Progressive Pulmonary Fibrosis:

1. Confirm progression criteria: FVC decline ≥10% predicted within 24 months, OR FVC decline 5-10% predicted PLUS worsening respiratory symptoms or increased fibrosis on imaging within 24 months 1
2. Consider nintedanib after failure of standard management for the underlying ILD 1
3. Quality of evidence is low to moderate, but conditional recommendation supports use 1, 4

Special Population Considerations:

• Elderly patients (≥75 years): Efficacy maintained (FVC benefit 105.3 ml/year vs placebo), but discontinuation rates higher (26.4% vs 16.0% in younger patients) 5
• Multiple comorbidities (≥5): Efficacy preserved (FVC benefit 139.3 ml/year), though discontinuation rates slightly higher (20.5% vs 15.7%) 5
• Chronic kidney disease: Standard 150 mg twice daily for CrCl >30 mL/min; consider starting at 100 mg twice daily for CrCl <30 mL/min 4
• Familial pulmonary fibrosis: Real-world data suggest less responsiveness to nintedanib, though survival appears similar 6

Adverse Effect Management

Gastrointestinal Effects (Most Common):

• Diarrhea occurs in approximately 62% of patients (vs 18% placebo) 1, 2
• Nausea: 3.1 times more frequent 1, 4
• Vomiting: 3.6 times more frequent 1, 4
• Abdominal pain: 4.2 times more frequent 1, 4
• Weight loss: 3.7 times more frequent 1, 4

Management strategy for persistent diarrhea:

1. Reduce dose to 100 mg twice daily - this manages symptoms in most patients 1
2. Consider temporary treatment interruption if dose reduction insufficient 1
3. Use anti-diarrheal medications as needed 7
4. Do NOT discontinue prematurely without attempting dose reduction 1

Hepatotoxicity:

• AST elevation: 3.2 times more frequent 1, 4
• ALT elevation: 3.6 times more frequent 1, 4

Monitoring protocol:

• Perform liver function tests monthly for first 3 months, then every 3 months 1
• Simultaneously monitor for diarrhea and weight loss 1

Treatment Discontinuation:

• Adverse events lead to permanent dose reduction 7.9 times more frequently than placebo 1, 4
• Treatment discontinuation occurs 1.9 times more frequently (but diarrhea leads to discontinuation in <5% of patients) 2, 7

Combination Therapy Considerations

Nintedanib can be combined with mycophenolate mofetil in systemic sclerosis-associated ILD with UIP pattern, which may provide additive benefit per the SENSCIS trial 1

Supportive Care

Aggressive supportive measures should accompany nintedanib treatment: 1

• GERD management with proton pump inhibitors
• Treatment of infections
• Pulmonary rehabilitation

Critical Caveats

• Nintedanib slows disease progression but does not reverse existing fibrosis 4
• Early treatment initiation preserves more lung function - do not delay 1
• Proactive adverse event management is essential to keep patients on therapy 5, 7
• The primary benefit is slowing FVC decline; mortality benefit remains unproven 3
• Real-world data confirm the clinical trial safety profile with no unexpected adverse events 7