What is the recommended dosing of nintedanib for progressive fibrosing interstitial lung disease, and how should the dose be adjusted or monitored in patients with hepatic impairment, renal impairment, advanced age, or pregnancy?

Nintedanib Dosing in Progressive Fibrosing Interstitial Lung Disease

Standard Dosing Recommendation

The recommended dose of nintedanib for progressive fibrosing ILD is 150 mg orally twice daily, with dose reduction to 100 mg twice daily reserved only for patients who cannot tolerate the standard dose due to adverse effects, particularly gastrointestinal symptoms. 1, 2

Initial Dosing Strategy

• Start all patients at 150 mg twice daily unless contraindicated, as this is the approved therapeutic dose that demonstrated efficacy in clinical trials 1, 2, 3
• The 150 mg twice daily dose reduced annual FVC decline by approximately 125 ml compared to placebo in IPF trials and 102.7 ml/year in progressive fibrosing ILD 1, 3
• Do not initiate at lower doses preemptively, as the 100 mg dose is only for management of intolerance, not as a starting strategy 4, 2

Dose Reduction Protocol

• Reduce to 100 mg twice daily only when patients experience persistent adverse effects that are not manageable with supportive care 1, 4, 2
• Approximately 27.9% of patients required dose reduction in clinical trials, primarily for gastrointestinal symptoms 5
• Consider temporary treatment interruption before permanent dose reduction if adverse effects are severe but potentially reversible 4, 5
• Permanent discontinuation should be reserved for patients who cannot tolerate even the reduced dose or develop serious hepatotoxicity 4, 5

Adverse Effect Management

Gastrointestinal Effects (Most Common)

• Diarrhea occurs in 62-76% of patients on nintedanib versus 18% on placebo, but leads to discontinuation in less than 5% 4, 3, 5
• Manage diarrhea with loperamide and dietary modifications before dose reduction 5
• Nausea (3.1-fold increase), vomiting (3.6-fold increase), and abdominal pain (4.2-fold increase) are common but usually manageable 4, 6
• Weight loss occurs 3.7-fold more frequently and requires nutritional monitoring and support 4, 6

Hepatotoxicity Monitoring

• Monitor liver enzymes (AST/ALT) monthly for the first 3 months, then every 3 months thereafter 1, 4
• AST elevations occur 3.2-fold more frequently and ALT elevations 3.6-fold more frequently than placebo 4, 6
• Reduce dose or interrupt treatment for transaminase elevations ≥3 times upper limit of normal 7, 5
• Permanently discontinue if liver enzyme elevations do not resolve after dose reduction 4

Special Population Considerations

Hepatic Impairment

• Contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) 7
• Use with caution in mild hepatic impairment with enhanced monitoring 7
• Female patients have a 3-4 fold higher exposure-adjusted risk of liver enzyme elevations compared to males 7

Renal Impairment

• No dose adjustment needed for mild to moderate chronic kidney disease (CrCl >30 mL/min) 6
• Consider starting at 100 mg twice daily with careful monitoring in severe CKD (CrCl <30 mL/min), though data are limited 6, 2
• Nintedanib exposure is not significantly affected by renal function, so dose adjustment based on renal function alone is not warranted 7

Advanced Age

• No specific dose adjustment required based on age alone 7
• Elderly patients may require more careful monitoring for adverse effects and weight loss 4

Pregnancy

• Contraindicated in pregnancy due to potential teratogenic effects from VEGF receptor inhibition 7
• Women of childbearing potential must use effective contraception during treatment 7

Combination Therapy Considerations

• Nintedanib can be combined with mycophenolate mofetil in systemic sclerosis-associated ILD, with similar adverse event profiles 1
• The relative treatment effect of nintedanib was consistent whether patients were taking MMF (26.3 ml/year FVC benefit) or not (55.4 ml/year benefit) 1
• Combination with pirfenidone increases gastrointestinal adverse events (69.8% vs 52.9% with nintedanib alone) but is manageable in selected patients 8
• Generally avoid combination therapy in non-progressive disease due to cost, adverse effects, and limited efficacy data 6

Monitoring Algorithm

1. Baseline: Liver function tests, weight, nutritional assessment 1, 4
2. Months 1-3: Monthly liver enzymes, assess for diarrhea and weight loss 1, 4
3. After Month 3: Liver enzymes every 3 months, ongoing GI symptom and weight monitoring 1, 4
4. Throughout treatment: Monitor for respiratory infections, provide aggressive GERD management with proton pump inhibitors 1

Common Pitfalls to Avoid

• Do not delay treatment initiation, as early treatment preserves more lung function 4
• Do not discontinue prematurely for diarrhea without attempting dose reduction to 100 mg twice daily 4
• Do not start at reduced doses preemptively in anticipation of adverse effects 2
• Do not ignore weight loss—implement nutritional support early 4, 6