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 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. 1

Idiopathic Pulmonary Fibrosis (IPF)

Indication and Patient Selection

• Nintedanib is conditionally recommended by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association for all patients with confirmed IPF regardless of disease severity. 1, 2
• Treatment should be initiated early in the disease course to preserve lung function. 1

Dosing for IPF

• Standard dose: 150 mg orally twice daily 1
• Dose reduction to 100 mg twice daily should be considered for patients who do not tolerate the standard dose. 1, 3
• Temporary treatment interruption may be necessary for persistent adverse effects. 1, 3

Efficacy in IPF

• Nintedanib reduces the annual rate of FVC decline by approximately 125 ml compared to placebo (difference of 125.3 ml in INPULSIS-1 and 93.7 ml in INPULSIS-2). 2, 4
• The drug reduces the risk of acute exacerbations of IPF (HR 0.38 in INPULSIS-2, though not significant in INPULSIS-1). 1, 4
• Nintedanib slows disease progression but does not reverse existing fibrosis and has not demonstrated a statistically significant mortality benefit (RR 0.70; 95% CI 0.47–1.03). 2

Progressive Pulmonary Fibrosis (PPF)

Indication for Non-IPF Fibrotic ILD

• Nintedanib is conditionally recommended for patients with progressive pulmonary fibrosis who have failed standard management. 1, 2
• The 2022 ATS/ERS/JRS/ALAT guidelines extend this recommendation to various types of fibrotic interstitial lung diseases manifesting PPF. 5, 2

Efficacy in PPF

• Nintedanib reduces annual FVC decline by approximately 107 ml compared to placebo in all patients with PPF. 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 demonstrated in fibrotic hypersensitivity pneumonitis, sarcoidosis, or unclassifiable ILD
• Nintedanib decreases the risk of ILD progression 2.4 times overall, though this benefit is primarily seen in patients with radiological UIP pattern (2.3 times) rather than non-UIP pattern. 5, 3
• No significant difference in all-cause mortality was demonstrated in the INBUILD trial. 5

Non-Small Cell Lung Cancer (NSCLC)

Indication and Dosing

• Nintedanib is indicated at 200 mg twice daily in combination with docetaxel as second-line therapy for advanced NSCLC of adenocarcinoma histology after progression on first-line chemotherapy. 1
• In patients with NSCLC and concurrent IPF, carboplatin plus nab-paclitaxel with nintedanib 150 mg twice daily improved overall survival in patients with nonsquamous histology (HR 0.61; 95% CI 0.40-0.93). 6

Mechanism of Action

• Nintedanib is an intracellular inhibitor of multiple tyrosine kinases targeting VEGF, FGF, and PDGF receptors, which are critical for angiogenesis and fibrosis. 1, 3, 7
• The drug reaches maximum plasma concentrations 2-4 hours after oral administration with a terminal elimination half-life of 10-15 hours. 7
• Nintedanib is metabolized via hydrolytic ester cleavage and glucuronidation, with less than 1% eliminated in urine. 7

Adverse Effects and Management

Gastrointestinal Effects (Most Common)

• Diarrhea occurs in approximately 62% of patients on nintedanib versus 18% on placebo. 1, 4
• Abdominal pain is 4.2 times more frequent than placebo. 5, 3
• Nausea is 3.1 times more frequent, vomiting 3.6 times more frequent. 5, 3
• Anorexia is 2.8 times more frequent, weight loss 3.7 times more frequent. 5, 3

Hepatic Effects

• Elevated AST occurs 3.2 times more frequently than placebo. 5, 3
• Elevated ALT occurs 3.6 times more frequently than placebo. 5, 3
• Liver function tests should be performed regularly during treatment. 3, 8

Treatment Discontinuation

• Adverse events leading to permanent dose reduction occur 7.9 times more frequently with nintedanib. 5, 3
• Adverse events leading to treatment discontinuation occur 1.9 times more frequently. 5, 3
• Diarrhea led to discontinuation in less than 5% of patients in the INPULSIS trials. 4

Management Algorithm

• For persistent diarrhea or other significant adverse effects, reduce dose to 100 mg twice daily or temporarily interrupt treatment. 1, 3
• Patient education and proactive management at treatment initiation minimize risk of permanent discontinuation. 8
• Monitor liver enzymes regularly and adjust dose accordingly in patients with mild hepatic impairment. 7, 8

Special Populations and Contraindications

Hepatic Impairment

• Nintedanib is not recommended in patients with moderate or severe hepatic impairment. 7
• Patients with mild hepatic impairment should be monitored closely with dose adjustment as needed. 7

Renal Impairment

• Renal function has no influence on nintedanib pharmacokinetics. 7
• Standard dose of 150 mg twice daily can be used in patients with mild to moderate CKD (creatinine clearance > 30 mL/min). 3
• Consider starting at reduced dose of 100 mg twice daily in severe CKD (creatinine clearance < 30 mL/min). 3

Drug Interactions

• Nintedanib has low potential for drug-drug interactions with cytochrome P450-metabolized drugs. 7
• Concomitant treatment with potent P-glycoprotein inhibitors or inducers can affect nintedanib pharmacokinetics. 7

Quality of Evidence Considerations

• The quality of evidence for nintedanib in PPF is rated as low to moderate, meaning the estimated effects should be interpreted with caution. 5, 3
• The quality of evidence was moderate for disease progression but low for mortality outcomes. 5
• Estimates for specific ILD subtypes are based on small sample sizes, particularly for sarcoidosis (n=12) and fibrotic occupational lung disease (n=39). 5