Switching to generic anti-epileptic medicines:A regulatory perspective

Introduction: Currently, there is a lot of discussion about whether generic substitution of anti-epileptic drugs (AEDs) with the same active moiety but from different manufacturers can take place safely. Many AEDs are considered to have a narrow therapeutic index, and the consequences of an epileptic attack are severe, in a physical, psychological and social respect. Therefore, there is ample ground to look critically at generic substitution of anti-epileptic medicines. In this context, the Dutch regulatory agency evaluated the exposureof generic AEDs and the occurrence of epilepsy related events. Methods: Reports received by the Dutch Pharmacovigilance Centre Lareb were screened for issues related to generic substitution of AEDs. Public literature dealing with generic substitution of AEDs was reviewed and checked for potential pharmacological issues related to generic substitution of AEDs. Finally, the exposures upon changing between different topiramate and gabapentin generics was evaluated based on internal bioequivalence data. Results: In only 26 of in total 2,103 reports in the Lareb database mentioning an AED as the suspected drug, a possible relationship was indicated with the substitution from a branded AED to a generic one. However, these data should be treated with care, since underreporting is a well-known phenomenon. The majority of publications on generic substitution of AEDs concerned potential instead of actual cases, with many publications based on surveys regarding prescribers' overall experience with switching. Potential issues raised in these publications relate to bioequivalence requirements, use of healthy volunteers instead of patients, variability in exposure, problems with medicine supply, and costs of adverse events. Overall, with very few exceptions, no differences in exposure upon generic substitution of AEDs were actually reported. Generic-generic substitution was also indicated as a potential problem. However, our investigations on topiramate and gabapentin generic-generic substitution indicated that this does not result in significant differences in exposure. Estimated ratios of AUC and Cmax upon substituting generics ranged from 94.1-113.1% and 91.2-103.1% for topiramate and from 95.6-114.9% and 92.5 111.5% for gabapentin, respectively. Conclusion: Overall, no evidence was found for a causal pharmacological relationship between switching to or between generic AEDs and the occurrence of epilepsy-related adverse events. Based on the strict requirements on generics, pharmacological differences between innovator and generic AEDs are considered unlikely, and have indeed hardly been reported. Alternative explanations for increased susceptibility to seizures with generic AEDs may be envisioned, like e.g., new or withdrawn co-medication, compliance, frequent switching, and differences in shape and colour of generics