Abstract: Objective To explore the characteristics of adverse drug reactions induced by leflunomide, such as hepatotoxicity, by using the FDA adverse event reporting system (FAERS) data in the United States, and to recommend that liver function should be closely monitored during clinical medication to prevent the hepatotoxicity of leflunomide. Methods The recommendations in the instructions and guidelines for the use of leflunomide among patients with liver damage in different countries were compared. The adverse event reports in FAERS data from January 1, 1999 to December 31, 2019 in the United States were mined by using the report ratio (ROR) method and the proportion report ratio (PRR) method. The signals of liver injury caused by leflunomide were mined, and the demographic characteristics, primary diseases, concomitant medications, clinical outcomes and other information were analyzed. Results Contraindications of leflunomide in Chinese instructions included severe liver damage, which was too broad compared with instructions or guidelines recommended by other countries. The US instructions deliberately added a black box to warn reports of severe liver damage and fatal liver failure to prevent this drug from being used by patients with a previous liver disease history or ALT>2 times the normal value. A total number of 28 186 adverse events of flunomide were retrieved, 4 319 (17.9%) of which were hepatotoxic adverse events. The ROR and PRR of hepatotoxicity of leflunomide and other drugs were 51.6 and 43.9 respectively. There were 3.5 times as many female patients with liver damage as male ones. The percentage of patients aged 46 to 60 was the highest (35.1%). Rheumatoid arthritis was the dominating primary disease, accounting for 77.5%. In terms of combined medication, 2 288 patients were treated with flunomide alone, accounting for 52.98%, while those treated with one to five types of drugs made up 29.22%. The combined use of adalimumab, glucocorticoid, non-steroidal anti-inflammatory drugs and methotrexate was the most common. The risk of death was mainly related to age and gender, and had no obvious correlations with the types of combined drugs, but tended to increase in male and elder patients. Conclusion Clinicians should be alert to the hepatotoxicity of leflunomide in China, and the liver function of patients should be monitored at an intervals of 2~4 weeks. Patients with a history of liver desease should avoid using this drug.

Key words: leflunomide, liver injury, FDA adverse event reporting system (FAERS), adverse drug reaction (ADR)