Bioequivalence and switchability of generic antiseizure medications (ASMs): A re‐appraisal based on analysis of generic ASM products approved in Europe

Abstract

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra‐subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow‐therapeutic‐index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second‐generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%–111%) applied to NTI drugs. Intra‐subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra‐subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non‐bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

Evaluating Therapeutic Equivalence of Generic and Original Levetiracetam in Patients with Epilepsy: A Retrospective Study

“…The generic levetiracetam approval was based on bioequivalence data determined by in vitro dissolution time profiles compared to the original brand. The latest publication by Odi et al [ 31 ] indicates that the risk of non-bioequivalence between individual generic brands of levetiracetam available in Europe is minimal, and varying among these products is unlikely to result in clinically relevant changes in plasma drug concentrations. However, the generic brands of levetiracetam mentioned in the European study are different from the brand examined in this study.…”

Therapeutic Basis of Generic Substitution of Antiseizure Medications

“…There are some reports that concludes that generic ASMs pose few issues as compared to branded versions (Holtkamp and Theodore, 2018;Kesselheim et al, 2010Kesselheim et al, , 2013Odi et al, 2021;Piñeyro-López et al, 2009;Privitera et al, 2016). In particular, Holtkamp and Theodore suggest that the high switchback rates for patients who switch to generic ASMs and then back to brand-name ASMs has more to do with improper administration of medication, rather than differing pharmacokinetics and pharmacodynamics between generic and brand-name ASMs.…”

“…They assert that potential issues arise when switching is done between different generic ASMs. The potential risks of switching from one generic to another is lessened when products meet NTI criteria for bioequivalence and have little difference in their pharmacokinetic parameters (Odi et al, 2021).…”

Bioequivalence, Drugs with Narrow Therapeutic Index and the Phenomenon of Biocreep: A Critical Analysis of the System for Generic Substitution

“…Even the FDA does not provide a comprehensive list, but NTI medications requiring stricter bioequivalence can be identified from product-specific guidance. For example, carbamazepine, everolimus, phenytoin, warfarin, digoxin, and valproic acid are considered NTI drugs that are subject to stricter bioequivalence requirements [ 46 ].…”