Changes in Warnings and Contraindications in Prescription Drug Labeling Due to Liver Toxicity

Abstract

Issuing labeling changes is a common practice to warn about important side effects after drug approval. Among the many safety concerns, liver toxicity is frequently a major cause for postapproval labeling changes. To examine labeling changes associated with liver toxicity, safety-related labeling changes due to liver toxicity were reviewed. They were categorized into labeling changes that clarified/emphasized existing safety information and those that added new safety information. For labeling changes with new safety information, the preapproval safety data were reviewed to evaluate whether there was strong evidence of liver toxicity in the preapproval clinical data.

Thirty-five labeling changes were found to meet the selection criteria. Among them, 10 modified “Boxed Warning,” 24 modified “Warnings,” and 12 modified “Contraindications.” If categorized by nature, 22 changes clarified/ emphasized existing information and eight added new information on liver toxicity.

The review of the preapproval safety data of drugs with labeling changes that added new information on liver toxicity demonstrated that only seven events of mild liver toxicity were associated with atomoxetine, and for telithromycin, the rates of combined elevation of bilirubin and aminotransferases and of pure elevation of aminotransferases were comparable with the comparator.

In conclusion, after drug approval, labeling changes are occasionally issued to warn of liver toxicity. They clarified/emphasized existing liver toxicity information more often than added new information. For drugs not considered he-patotoxic initially but found to be associated with significant liver toxicity concern after drug approval, no strong evidence of liver toxicity could be noted in the preapproval data sets.