Purpose of Review <p>The comparison between generic and brand-name formulations of anti-seizure medications is a topic of great clinical relevance. While generic ASMs are typically significantly cheaper than their brand counterparts, any significant pharmacokinetic differences between formulations could lead to life-threatening worsening of seizure frequency and other adverse side effects. Bioequivalence standards for medications are set nationally in the United States by the Food and Drug Administration (FDA), though there is concern that these standards are not strict enough in the case of ASMs. This paper summarizes the existing literature regarding brand-to-generic substitutions of ASMs.</p> Recent Findings <p>There have been numerous clinical trials demonstrating bioequivalance between formulations as well as anecdotal evidence describing seizure worsening with the substitution of several medications. The most notable of these trials, the Equivalence among Generic Antiepileptic Drugs (EQUIGEN) study, showed bioequivalence among brand and disparate generic formulations of lamotrigine, a medication with described sensitivity to worsening seizure frequency among epilepsy patients. After the EQUIGEN study, the American Epilepsy Society amended its previous position in 2017 to state that FDA standards for bioequivalence are appropriate for ASMs. Because of conflicting data in other smaller studies, there remains a lack of comfort among some providers and patients with making substitutions.</p> Summary <p>Controlled trials have demonstrated bioequivalence for brand name versus generic ASM formulations, though some patients and providers continue to demonstrate hesitancy with making generic substitutions. For these reasons, generic substitutions of ASMs should be performed with a shared-decision making model and informed consent.</p>