What is the recommended use and dosing of Nintedanib (generic name) for idiopathic pulmonary fibrosis and non-small cell lung cancer?

Nintedanib: Recommended Use and Dosing

Nintedanib should be initiated at 150 mg twice daily for idiopathic pulmonary fibrosis (IPF) to slow disease progression, and at 200 mg twice daily in combination with docetaxel for second-line treatment of adenocarcinoma non-small cell lung cancer (NSCLC). 1

Idiopathic Pulmonary Fibrosis (IPF)

Indication and Patient Selection

• Nintedanib is indicated for all patients with confirmed IPF regardless of disease severity. 1
• Treatment should be initiated early in the disease course to maximize lung function preservation. 1
• The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association conditionally recommend nintedanib for IPF based on its ability to slow disease progression. 2

Dosing for IPF

• Standard dose: 150 mg orally twice daily. 1
• For patients who cannot tolerate the standard dose due to adverse effects, reduce to 100 mg twice daily or temporarily interrupt treatment. 1, 3
• In patients with severe chronic kidney disease (creatinine clearance <30 mL/min), consider starting at the reduced dose of 100 mg twice daily with careful monitoring. 3

Efficacy in IPF

• Nintedanib reduces the annual rate of FVC decline by approximately 125 ml compared to placebo (125.3 ml in INPULSIS-1 and 93.7 ml in INPULSIS-2). 4, 2
• The drug reduces the risk of acute exacerbations of IPF (HR 0.16; 95% CI, 0.04-0.70). 1
• Nintedanib does not demonstrate a statistically significant mortality benefit (RR 0.70; 95% CI 0.47-1.03), though it slows disease progression. 2

Progressive Pulmonary Fibrosis (PPF) Beyond IPF

Indication

• Nintedanib is conditionally recommended for progressive pulmonary fibrosis in patients with non-IPF fibrotic interstitial lung diseases who have failed standard management. 1, 2

Efficacy in PPF

• Among all patients with PPF, nintedanib reduces annual FVC decline by approximately 107 ml compared to placebo. 5, 1, 3
• The benefit varies significantly by underlying disease type: 5, 1, 3
  • CTD-related ILD: 106.2 ml/yr less decline
  • Fibrotic NSIP: 141.7 ml/yr less decline
  • Fibrotic occupational lung disease: 252.8 ml/yr less decline
  • No significant benefit in fibrotic hypersensitivity pneumonitis, sarcoidosis, or unclassifiable ILD
• Nintedanib decreases the risk of ILD progression 2.4 times overall. 3
• The quality of evidence for PPF is rated as low to moderate, requiring cautious interpretation. 5, 3

Non-Small Cell Lung Cancer (NSCLC)

Indication

• Nintedanib 200 mg twice daily is administered in combination with docetaxel as second-line therapy for advanced NSCLC of adenocarcinoma histology after progression on first-line chemotherapy. 1

Efficacy in NSCLC

• In patients with NSCLC and IPF, carboplatin plus nab-paclitaxel with nintedanib improved overall survival specifically in patients with nonsquamous histology (HR 0.61; 95% CI 0.40-0.93). 6
• Median progression-free survival was 6.2 months with nintedanib plus chemotherapy versus 5.5 months with chemotherapy alone (HR 0.68; 95% CI 0.50-0.92). 6

Mechanism of Action

• Nintedanib is an intracellular inhibitor of multiple tyrosine kinases targeting VEGF, FGF, and PDGF receptors. 1, 3, 4
• The drug has high total clearance (1390 mL/min), high volume of distribution (1050 L), and absolute bioavailability slightly below 5%. 7
• Renal clearance is negligible (approximately 20 mL/min), with urinary excretion of only 1% of the dose. 7

Adverse Effects and Management

Common Gastrointestinal Effects

• Diarrhea is the most common adverse effect, occurring in approximately 62% of patients versus 18% on placebo. 1, 2
• Other gastrointestinal effects include: 5, 3
  • Abdominal pain (4.2 times more frequent than placebo)
  • Nausea (3.1 times more frequent)
  • Vomiting (3.6 times more frequent)
  • Anorexia (2.8 times more frequent)
  • Weight loss (3.7 times more frequent)

Hepatic Effects

• Elevated liver enzymes occur frequently: 5, 3
  • AST elevation (3.2 times more frequent than placebo)
  • ALT elevation (3.6 times more frequent than placebo)
• Regular liver function monitoring is required. 3

Treatment Modifications

• Adverse events lead to permanent dose reduction 7.9 times more frequently than placebo. 5, 3
• Treatment discontinuation due to adverse events occurs 1.9 times more frequently than placebo. 5, 3
• For persistent diarrhea or other significant adverse effects, reduce dose to 100 mg twice daily or temporarily interrupt treatment. 1, 3
• Diarrhea led to discontinuation in less than 5% of patients in the INPULSIS trials. 4

Critical Caveats

• Nintedanib slows disease progression but does not reverse existing fibrosis. 3
• The drug shows no significant difference in respiratory adverse events (cough, dyspnea, bronchitis, nasopharyngitis), headache, serious adverse events, or severe adverse events compared to placebo. 5
• Steady state is reached within 7 days of twice-daily dosing, with negligible accumulation after repeated administration. 7
• In the INBUILD trial for PPF, estimates for specific ILD subtypes are based on small sample sizes, limiting confidence in subgroup analyses. 5