PIRFENIDONE

5 WARNINGS AND PRECAUTIONS Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with pirfenidone including cases of drug-induced liver injury. In the postmarketing setting, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcomes, have been reported. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required. ( 2.1 , 5.1 ) Photosensitivity and rash: Photosensitivity and rash have been noted with pirfenidone. Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing daily. Temporary dosage reductions or discontinuations may be required. ( 5.2 ) Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastroesophageal reflux disease, and abdominal pain have occurred with pirfenidone. Temporary dosage reductions or discontinuations may be required. ( 5.3 ) 5.1 Elevated Liver Enzymes and Drug-Induced Liver Injury Cases of drug-induced liver injury (DILI) have been observed with pirfenidone. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Patients treated with pirfenidone 2403 mg/day in three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥3 × ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations ≥10 × ULN in ALT or AST occurred in 0.3% of patients in the pirfenidone 2403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST ≥3 × ULN were reversible with dose modification or treatment discontinuation. Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with pirfenidone, monthly for the first 6 months, every 3 months thereafter, and as clinically indicated. Measure liver function tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dosage modification or interruption may be necessary for liver enzyme elevations [see Dosage and Administration (2.1 , 2.3) ] . 5.2 Photosensitivity Reaction or Rash Patients treated with pirfenidone 2403 mg/day in the three Phase 3 studies had a higher incidence of photosensitivity reactions (9%) compared with patients treated with placebo (1%). The majority of the photosensitivity reactions occurred during the initial 6 months. Instruct patients to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, instruct patients to avoid concomitant medications known to cause photosensitivity. Dosage reduction or discontinuation may be necessary in some cases of photosensitivity reaction or rash [see Dosage and Administration (2.3) ] . 5.3 Gastrointestinal Disorders In the clinical studies, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, gastro-esophageal reflux disease, and abdominal pain were more frequently reported by patients in the pirfenidone treatment groups than in those taking placebo. Dosage reduction or interruption for gastrointestinal events was required in 18.5% of patients in the 2403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of patients in the pirfenidone 2403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (>2%) gastrointestinal events that led to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. The incidence of gastrointestinal events was highest early in the course of treatment (with highest incidence occurring during the initial 3 months) and decreased over time. Dosage modifications may be necessary in some cases of gastrointestinal adverse reactions [see Dosage and Administration (2.3) ] .