What is the recommended dosing, monitoring, contraindications, side effects, and alternative therapy for pirfenidone in adult patients with idiopathic pulmonary fibrosis?

Pirfenidone for Idiopathic Pulmonary Fibrosis

Pirfenidone is indicated for treatment of idiopathic pulmonary fibrosis (IPF) and should be initiated at 267 mg three times daily with food, titrated over 14 days to the maintenance dose of 801 mg three times daily (2,403 mg/day total). 1

Dosing and Administration

Initial Titration Schedule

• Days 1-7: 267 mg three times daily (801 mg/day total) 1
• Days 8-14: 534 mg three times daily (1,602 mg/day total) 1
• Day 15 onward: 801 mg three times daily (2,403 mg/day total) 1

All doses must be taken with food at the same time each day to minimize gastrointestinal side effects. 1 Doses above 2,403 mg/day are not recommended. 1

Dose Interruption Guidelines

• If treatment interrupted <14 days: Resume at previous dose without re-titration 1
• If treatment interrupted ≥14 days: Must restart with full 14-day titration schedule 1

Mandatory Pre-Treatment and Monitoring Requirements

Baseline Testing

Obtain liver function tests (ALT, AST, bilirubin) before initiating pirfenidone. 1

Ongoing Monitoring

• Liver enzymes: Monthly for first 6 months, then every 3 months thereafter 2
• Pulmonary function tests (FVC, DLCO): Every 3-6 months to assess treatment response 2, 3
• Annual vaccinations: Influenza and pneumococcal vaccines strongly recommended 2

Contraindications and Drug Interactions

Absolute Contraindications

None listed in FDA labeling. 1

Critical Drug Interactions Requiring Dose Adjustment

• Strong CYP1A2 inhibitors (fluvoxamine, enoxacin): Reduce pirfenidone to 267 mg three times daily (801 mg/day total) 1
• Moderate CYP1A2 inhibitors (ciprofloxacin 750 mg twice daily): Reduce pirfenidone to 534 mg three times daily (1,602 mg/day total) 1

Dose Modifications for Adverse Effects

Liver Enzyme Elevations

ALT/AST >3 but ≤5 × ULN without symptoms:

• Discontinue confounding medications and monitor closely 1
• May maintain full dose, reduce dose, or temporarily interrupt until liver enzymes normalize 1

ALT/AST >3 but ≤5 × ULN WITH symptoms or hyperbilirubinemia:

• Permanently discontinue pirfenidone; do not rechallenge 1

ALT/AST >5 × ULN:

• Permanently discontinue pirfenidone; do not rechallenge 1

Other Adverse Reactions

For significant gastrointestinal symptoms, photosensitivity, or rash, consider temporary dose reduction or interruption until symptoms resolve. 1

Common Side Effects and Management

Most Frequent Adverse Events (≥10% incidence)

• Gastrointestinal: Nausea (37.6%), diarrhea (28.1%), dyspepsia (18.4%), vomiting (15.9%), abdominal pain 4, 5
• Dermatologic: Rash (25-32%), photosensitivity (12%) 4, 5
• Other: Fatigue, headache, decreased appetite, dizziness, weight loss 1

Management Strategies

Gastrointestinal symptoms: Generally mild to moderate; take with food, consider temporary dose reduction 4, 6

Photosensitivity and rash:

• Avoid sunlight and sunlamps 1
• Use sunscreen and protective clothing daily 2, 1
• Consider temporary dose reduction or interruption 1

Severe Cutaneous Adverse Reactions (SCAR)

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS have been reported postmarketing. 1 If SCAR is suspected, interrupt pirfenidone immediately; if confirmed, permanently discontinue. 1

Efficacy Data

Impact on Disease Progression

Pirfenidone reduces the rate of FVC decline in mild to moderate IPF (FVC >50% predicted, DLCO >35% predicted). 2, 5 In the CAPACITY 004 trial, mean FVC decline at 72 weeks was -8.0% with pirfenidone versus -12.4% with placebo (difference 4.4%, p=0.001). 5

Mortality Benefit

Pooled analysis across clinical trials demonstrated significant reduction in IPF-related mortality (3% vs 7%) and all-cause mortality (6% vs 8%) compared to placebo. 6, 5

Alternative Therapy

Nintedanib is the primary alternative antifibrotic agent for IPF. 7, 2 For progressive pulmonary fibrosis (PPF) in non-IPF interstitial lung diseases, nintedanib has a conditional recommendation as first-line therapy after failure of standard management. 7, 3

Therapies to Avoid

• Triple therapy (prednisone + azathioprine + N-acetylcysteine): Increases mortality in IPF; do NOT use 2, 3
• Corticosteroid monotherapy: Not recommended except for incapacitating cough or acute exacerbations 2
• Ambrisentan: Contraindicated in IPF 2

Use in Progressive Pulmonary Fibrosis (Non-IPF)

For PPF in non-IPF interstitial lung diseases, evidence for pirfenidone is very low quality, with only a conditional recommendation (62% committee support, 38% abstained due to insufficient evidence). 7 The guideline committee recommends further research into pirfenidone efficacy for specific non-IPF ILD subtypes manifesting PPF. 7

Pirfenidone increased gastrointestinal discomfort 1.8-fold and photosensitivity 4.9-fold in PPF trials, with no statistically significant mortality benefit demonstrated. 7

Long-Term Safety Profile

Comprehensive analysis of 1,299 patients followed for up to 9.9 years (3,160 person-years exposure) demonstrated that pirfenidone is safe and generally well tolerated long-term. 4 Adverse events were predominantly mild to moderate, with only 3.1% experiencing ALT/AST elevations >3 × ULN (adjusted incidence 2.3 per 100 person-years), which were generally transient and reversible with dose modification. 4