| toxicity summary | IDENTIFICATION AND USE: Pirfenidone is a white solid. It is used as medication for the treatment of idiopathic pulmonary fibrosis. HUMAN EXPOSURE AND TOXICITY: Reports of angioedema such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been reported with use of pirfenidone in the post-marketing setting. ANIMAL STUDIES: In a 24-month carcinogenicity study in rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above . There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1500 mg/kg/day . In a 24-month carcinogenicity study in mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above . There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above . Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1000 mg/kg/day . A fertility and embryo-fetal development study with rats and an embryo-fetal development study with rabbits that received oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose in adults revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles were seen in rats at doses approximately equal to and higher than the MRDD in adults . In a pre- and post-natal development study, prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults . Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice. No genotoxic effects were observed neither in newborn rats transplacentally exposed to pirfenidone, or in two adult rodent models when pirfenidone was administered orally or topically. |
