What are the approved indications, dosing regimens, and monitoring requirements for nintedanib?

Nintedanib Indications, Dosing, and Monitoring

Approved Indications

Nintedanib is FDA-approved for three primary indications: idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), and progressive fibrosing interstitial lung diseases (PF-ILD). 1

Specific Disease States

• Idiopathic Pulmonary Fibrosis: Nintedanib is indicated for all patients with confirmed IPF diagnosis regardless of disease severity, and should be initiated early in the disease course to preserve lung function 1

• Systemic Sclerosis-Associated ILD: Nintedanib should be considered alone or in combination with mycophenolate mofetil (MMF) for treatment of SSc-ILD 2

• Progressive Fibrosing ILD: Nintedanib is indicated for patients with non-IPF fibrotic interstitial lung diseases who demonstrate progression despite standard management 1

  • Progression is defined as: 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

• Sjögren's-Associated ILD: Nintedanib is approved for progressive fibrotic lung disease phenotype in Sjögren's syndrome 2

• Non-Small Cell Lung Cancer: Nintedanib 200 mg twice daily is approved as second-line therapy in combination with docetaxel for adenocarcinoma NSCLC after first-line chemotherapy progression 1

Standard Dosing Regimen

The approved therapeutic dose 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. 1, 3

Dosing Algorithm

• Initial dose: Start ALL eligible patients at 150 mg twice daily 3

  • This is the dose that demonstrated efficacy in clinical trials, reducing annual FVC decline by approximately 125 ml in IPF 1, 4 and 107 ml in PF-ILD 1, 5

• Dose reduction: Reduce to 100 mg twice daily ONLY when patients experience persistent adverse effects that cannot be adequately managed with supportive care 1, 3

  • Most commonly for persistent diarrhea or significant gastrointestinal symptoms 1

• Timing: Take with food to reduce gastrointestinal side effects 6

• Pharmacokinetics: Peak plasma concentrations occur 2-4 hours after administration, with terminal half-life of 10-15 hours and negligible accumulation with twice-daily dosing 6

Special Populations

• Hepatic impairment:

  • Mild: Monitor closely and adjust dose accordingly 6
  • Moderate to severe: NOT recommended 6

• Renal impairment: No dose adjustment required; renal function does not influence nintedanib pharmacokinetics 6

• Elderly, low body weight, smoking: Effects are within inter-patient variability range; no dose adjustments required 6

Combination Therapy

Nintedanib can be combined with mycophenolate mofetil in SSc-ILD, showing similar adverse event profile to nintedanib alone. 1

Evidence for Combination Therapy

• In the SENSCIS trial, the relative treatment effect of nintedanib was similar whether patients were taking MMF (40% benefit) or not (46% benefit) 2

• The magnitude of FVC benefit: 26.3 ml/year additional preservation when combined with MMF versus 55.4 ml/year when used without MMF 2, 1

• The adverse event profile of nintedanib was generally similar with or without MMF 2

Monitoring Requirements

Baseline Assessment

• Obtain liver function tests (AST/ALT) 1
• Record body weight and perform nutritional assessment 1
• Confirm diagnosis with high-resolution CT and pulmonary function tests 2

Ongoing Monitoring Protocol

Months 1-3:

• Liver enzyme tests (AST/ALT) monthly 1, 3
• Evaluate for diarrhea and weight loss at each visit 1

After Month 3:

• Liver enzyme monitoring every 3 months 1, 3
• Pulmonary function tests every 3-6 months 2
• Ongoing surveillance for gastrointestinal symptoms and weight changes 1

Throughout treatment:

• Monitor for respiratory infections 1
• Aggressive management of gastroesophageal reflux disease with proton pump inhibitors 1

Hepatotoxicity Management

• AST elevation occurs 3.2-fold more frequently with nintedanib versus placebo 1
• ALT elevation occurs 3.6-fold more frequently with nintedanib versus placebo 1
• Clinically significant elevations that do not resolve after dose reduction may warrant permanent discontinuation 1

Adverse Event Profile and Management

Gastrointestinal Effects (Most Common)

Diarrhea is the most common adverse event, occurring in 62-76% of patients on nintedanib versus 18-32% on placebo. 2, 1, 4

• Management: Reduce dose to 100 mg twice daily for persistent diarrhea; this manages symptoms in most patients 1
• Anti-diarrheal medications can be used 7
• Treatment discontinuation due to diarrhea occurs in less than 5% of patients 4

Other gastrointestinal effects:

• Nausea: 3.1-fold more frequent 1
• Vomiting: 3.6-fold more frequent 1
• Abdominal pain: 4.2-fold more frequent 1
• Anorexia: 2.8-fold more frequent 1

Weight Loss

• Occurs 3.7-fold more frequently with nintedanib versus placebo 1
• Requires routine monitoring and nutritional support 1

Treatment Modification Rates

• Permanent dose reduction required 7.9-fold more often than placebo 1
• Overall treatment discontinuation due to adverse events occurs 1.9-fold more frequently than placebo 1

Respiratory and Serious Adverse Events

• No significant differences in respiratory adverse events (cough, dyspnea, bronchitis, nasopharyngitis) between nintedanib and placebo 1
• Incidence of serious or severe adverse events does not differ significantly from placebo 1
• Bleeding and cardiovascular adverse events are rarely reported 7

Clinical Efficacy Outcomes

Impact on Morbidity

In IPF: Nintedanib reduced adjusted annual FVC decline to -114.7 ml/year versus -239.9 ml/year with placebo (difference 125.3 ml; P<0.001) 4

In SSc-ILD: Annual rate of FVC change was -52.4 ml/year with nintedanib versus -93.3 ml/year with placebo (P=0.04) 2

In PF-ILD: Annual FVC decline was -80.8 ml/year with nintedanib versus -187.8 ml/year with placebo (difference 107.0 ml; P<0.001) 5

Acute Exacerbations

• In IPF, nintedanib reduces the risk of acute exacerbations (HR 0.16; 95% CI 0.04-0.70) 1
• Results varied between trials: INPULSIS-2 showed significant benefit (HR 0.38; P=0.005), while INPULSIS-1 showed no significant difference 4

Common Pitfalls and Caveats

• Do NOT delay treatment initiation: Early treatment preserves more lung function 1

• Do NOT discontinue prematurely for diarrhea: Attempt dose reduction to 100 mg twice daily before discontinuing 1

• Do NOT use in moderate-severe hepatic impairment: Contraindicated in these populations 6

• Drug interactions: Concomitant treatment with potent P-glycoprotein inhibitors or inducers can affect nintedanib pharmacokinetics 6

• Limited data in elderly and advanced disease: Some evidence suggests greater treatment discontinuation rates in these populations 7