Pharmacotherapeutic issues associated with generic substitutions of antiseizure medications (ASM) may not only be the result of the Food and Drug Administration’s (FDA) approved bioequivalence standards, according to a review published in the Journal of Pharmacology and Experimental Therapeutics.

Although ASMs offer seizure control for many, approximately 30% of patients have drug-resistant or intractable seizures. Generic substitution issues have been reported with ASMs such as phenytoin, topiramate, levetiracetam, carbamazepine, and lamotrigine, suggesting potential complications with switching, though the study authors noted, for most ASMs, the variability between the brand and generic is often less than 10% of the expected value.

“Overall, based on the published evidence on specific generic ASMs, FDA bioequivalence standards are not the cause of problems with generic ASM substitution,” the study authors explained. Findings of their analysis revealed generic ASMs “pose few issues” compared with brand products and that high switchback to brand versions may have more to do with patient perceptions and confusion, rather than pharmacokinetic issues.  

Proper patient education on what to expect when switching between a brand and generic product or between generics is imperative, according to the authors, as some studies have shown that even a pill color change can lead to significant nonadherence. Additionally, they suggest initiating treatment with a generic ASM, rather than a brand, to avoid confusion.

To further prevent adverse events associated with generic substitutions, the authors recommend that all ASMs be considered narrow therapeutic index (NTI) drugs.  With NTI drugs, even a slight difference in dose or blood concentration can lead to therapeutic failure or adverse drug reactions. Bioequivalence studies for generic versions of NTI drugs are more complex and allow only a narrow margin of pharmacokinetic difference between the generic and brand product. 

“ASM drug products with NTI designation will better serve the needs of epilepsy patients because they are better regulated for effective drug delivery with consistent clinical response,” the authors concluded.


Elmer S, Reddy DS. Therapeutic basis of generic substitution of antiseizure medications. J Pharmacol Exp Ther. Published online March 3, 2022. doi: 10.1124/jpet.121.000994.