Black-Box Warnings of Antiseizure Medications: What is Inside the Box?

Abstract

Antiseizure medications can cause serious adverse reactions and have deleterious drug interactions that often complicate the clinical management of patients. When the US Food and Drug Administration (FDA) wants to alert healthcare providers and patients about the risk of potentially serious or fatal drug reactions, the FDA requires the manufacturers of these medications to format these warnings within a "black-box" border, and prominently display this box on the first section of the package insert; such warnings are called "black-box warnings (BBWs)". The BBW is a way for the FDA to urge physicians to evaluate patients more rigorously and carefully weigh the risks and benefits, before prescribing medication that has the potential to cause serious adverse reactions, and to formulate a plan for close monitoring during therapy. The FDA BBW provides the extra layer of safety but many healthcare providers fail to comply with these warnings. Currently, there are 26 FDA-approved antiseizure medications in the US market, 38% of which have received BBWs, and most of the antiseizure medications with BBWs are older-generation drugs. Some antiseizure medications have multiple BBWs; for example, valproic acid has three BBWs including hepatotoxicity, fetal risk, and pancreatitis, carbamazepine has BBWs of serious skin and hematological reactions, and felbamate also has two BBWs including hepatic failure and aplastic anemia. The purpose of this review is to provide insight into each BBW received by antiseizure medications and discuss the FDA recommendations for evaluating the drug benefit/risk, and for monitoring parameters before the initiation of and during treatment.