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Cases of drug-induced liver injury (DILI) have been reported in patients receiving pirfenidone. During the post-marketing period, both non-serious and serious cases of DILI have been documented, including severe liver injury resulting in death. In the three Phase 3 trials, the incidence of elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 3× the upper limit of normal (ULN) was higher in patients treated with pirfenidone 2403 mg daily than in those receiving placebo (3.7% vs. 0.8%, respectively). Elevations in ALT or AST levels ≥ 10× ULN occurred in 0.3% of patients in the pirfenidone 2403 mg daily group and 0.2% of patients in the placebo group. Elevations in ALT and AST levels ≥ 3× ULN were reversible following dose adjustment or treatment discontinuation.
Liver function tests (ALT, AST, and bilirubin) should be performed before initiating pirfenidone treatment, once monthly during the first 6 months of treatment, once every 3 months thereafter, and as clinically indicated. For patients reporting symptoms that may indicate liver injury, including fatigue, anorexia, right upper quadrant discomfort, darkening of urine, or jaundice, liver function tests should be conducted promptly. Dose adjustment or treatment interruption may be required for elevated liver enzymes.
In the three Phase 3 studies, the incidence of photosensitivity reactions was higher in patients treated with pirfenidone 2403 mg daily (9%) than in those receiving placebo (1%). Most photosensitivity reactions occurred within the first 6 months of treatment. Patients should be advised to avoid or minimize exposure to sunlight (including sunlamps), use sunscreen with a sun protection factor (SPF) of 50 or higher, and wear sun-protective clothing. In addition, patients should be instructed to avoid concomitant use of medications known to cause photosensitivity reactions. Dose reduction or treatment discontinuation may be necessary in some cases of photosensitivity reaction or rash.
During post-marketing surveillance, cases of severe cutaneous adverse reactions (SCAR) associated with pirfenidone use have been reported, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). If signs or symptoms of SCAR appear, pirfenidone treatment should be interrupted until the cause of the reaction is identified. Consultation with a dermatologist is recommended. If SCAR is confirmed, pirfenidone should be permanently discontinued.
In clinical studies, gastrointestinal events (nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease, and abdominal pain) were reported more frequently in patients in the pirfenidone treatment group than in those in the placebo group. In the 2403 mg daily group, 18.5% of patients required dose reduction or treatment interruption due to gastrointestinal events, compared with 5.8% in the placebo group; 2.2% of patients in the pirfenidone 2403 mg daily group discontinued treatment due to gastrointestinal events, versus 1.0% in the placebo group. The most common (> 2%) gastrointestinal events leading to dose reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia.
The incidence of gastrointestinal events was highest during the early phase of treatment (peaking within the first 3 months) and decreased over time. Dose adjustment may be required in some cases of gastrointestinal adverse reactions.
FDA，2023.02
