What is the recommended treatment for a patient with idiopathic pulmonary fibrosis (IPF), considering the use of Ofev (nintedanib)?

Nintedanib (Ofev) for Idiopathic Pulmonary Fibrosis

Nintedanib 150 mg twice daily is conditionally recommended for patients with IPF to slow disease progression by reducing the annual rate of FVC decline by approximately 125 ml compared to placebo. 1

Mechanism and Evidence Base

Nintedanib is an intracellular tyrosine kinase inhibitor targeting VEGF, FGF, and PDGF receptors. 1, 2 The INPULSIS-1 and INPULSIS-2 trials (n=1,066 patients) demonstrated that nintedanib significantly reduced the adjusted annual rate of FVC decline: -114.7 ml versus -239.9 ml with placebo (difference 125.3 ml) in INPULSIS-1, and -113.6 ml versus -207.3 ml with placebo (difference 93.7 ml) in INPULSIS-2. 1, 3

While nintedanib showed no mortality benefit (RR 0.70; 95% CI 0.44-1.11) when trials were pooled, it demonstrated a reduction in acute exacerbations (HR 0.16; 95% CI 0.04-0.70) in the phase 2 trial. 1 The INPULSIS trials showed mixed results on exacerbations, with INPULSIS-2 showing benefit (HR 0.38; 95% CI 0.19-0.77) but INPULSIS-1 showing no difference. 3

Patient Selection and Timing

• Initiate nintedanib at first identification of clinical or physiological impairment or documented decline in lung function. 2 Early treatment preserves more lung function before irreversible fibrosis develops. 2

• Nintedanib is indicated for confirmed IPF regardless of disease severity. 2 The efficacy is consistent across patients aged ≥75 years versus <75 years, and across varying comorbidity burdens. 4

• Do not withhold treatment based on age or comorbidities alone. 4 Real-world data from 5,717 Japanese patients confirmed safety and effectiveness similar to clinical trials. 5

Dosing and Administration

Standard dosing: 150 mg twice daily 1, 2

Dose reduction strategy for adverse events:

• Reduce to 100 mg twice daily for persistent diarrhea or significant GI symptoms 2, 6
• Temporary treatment interruption may be necessary for severe adverse events 2, 6
• In clinical trials, 27.9% of nintedanib patients required dose reduction versus 3.8% on placebo 6

Adverse Event Management

Gastrointestinal effects (most common):

• Diarrhea occurs in 62-63% of nintedanib patients versus 18% on placebo 1, 3, 5
• Despite high incidence, only 4.4% discontinued due to diarrhea 6
• Nausea (3.1 times more frequent), vomiting (3.6 times more frequent), abdominal pain (4.2 times more frequent) 2

Hepatic monitoring:

• Perform liver function tests monthly for 3 months, then every 3 months 2, 7
• AST elevation 3.2 times more frequent, ALT elevation 3.6 times more frequent 2
• Manage elevations through dose reduction or treatment interruption 6

Weight loss:

• Occurs 3.7 times more frequently than placebo 2
• Monitor weight regularly during therapy 2

Overall discontinuation rates:

• 19.3% discontinued due to adverse events in clinical trials 6
• Real-world Japanese data showed 44% discontinued due to adverse events at 24 months 5
• Proactive adverse event management is critical to keep patients on therapy 4

Special Considerations

Anticoagulation:

• Patients requiring anticoagulation for standard indications (atrial fibrillation, VTE, etc.) should receive anticoagulation according to standard guidelines 7
• Direct oral anticoagulants are preferred over warfarin when combining with nintedanib 7
• Do not use anticoagulation as treatment for IPF itself - warfarin showed trend toward increased mortality (RR 1.77; 95% CI 0.94-3.33) when used to treat IPF 7
• Monitor for bleeding complications, though risk remains low 7

Chronic kidney disease:

• Standard dose 150 mg twice daily for mild to moderate CKD (CrCl >30 mL/min) 8
• Consider starting at 100 mg twice daily for severe CKD (CrCl <30 mL/min) 8

Combination therapy:

• Nintedanib can be combined with mycophenolate in systemic sclerosis-associated ILD with UIP pattern 2
• Do not use combination of N-acetylcysteine, azathioprine, and prednisone - this was stopped early for harm 1

Common Pitfalls to Avoid

1. Discontinuing prematurely for diarrhea without attempting dose reduction - reduce to 100 mg twice daily first 2, 6

2. Delaying treatment initiation - early treatment preserves more lung function 2

3. Withholding treatment in elderly patients or those with comorbidities - efficacy is consistent across age groups and comorbidity burden 4

4. Using anticoagulation to treat IPF - only use anticoagulation for standard indications unrelated to IPF 7

5. Inadequate hepatic monitoring - liver function tests must be performed monthly initially, then quarterly 2, 7