Transaminase Levels and Hepatic Events During Tocilizumab Treatment: Pooled Analysis of Long‐Term Clinical Trial Safety Data in Rheumatoid Arthritis

Objective To investigate liver enzyme abnormalities and hepatic adverse events (AEs) during long‐term tocilizumab treatment for rheumatoid arthritis in clinical trials. Methods Data were pooled from patients who received intravenous tocilizumab (4, 8, or 10 mg/kg with or without disease‐modifying antirheumatic drugs [DMARDs]) in phase III or IV clinical trials, long‐term extensions, and a pharmacology study. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured routinely in these trials. AE rates were measured per 100 patient‐years of tocilizumab exposure for this pooled analysis. Results Overall, 16,204.8 patient‐years of tocilizumab exposure (mean ± SD duration of exposure 3.9 ± 2.0 years) were evaluated for 4,171 patients. ALT and AST elevations greater than the upper limit of normal (ULN) occurred in 70.6% and 59.4% of patients, respectively. ALT/AST elevations were >1–3× ULN in 59%/55% of patients, >3–5× ULN in 8.9%/3.3% of patients, and >5× ULN in 2.9%/0.9% of patients. Most elevations occurred during the first year of treatment. Single ALT/AST elevations >3× ULN occurred in 7.7%/3.6% of patients, and ≥2 consecutive elevations >3× ULN occurred in 1.9%/0.4% of patients. Elevations >3× ULN returned to normal in 80% of patients (median of 5.6 weeks to normalization). A total of 2.5% of patients withdrew from tocilizumab treatment following ALT/AST elevations. A total of 7 hepatic serious AEs (SAEs) (0.04 per 100 patient‐years [95% confidence interval 0.02–0.09]) occurred in the tocilizumab studies. Conclusion Transaminase elevations with tocilizumab were frequent, but rates of hepatic SAEs were low in this clinical trial data set. Regular monitoring, with dose adjustment of tocilizumab/DMARDs for persistent elevations, is recommended.