Abstract Details

Generic substitution of ASMs is a complex issue. It is thought that frequent generic substitution in people with epilepsy may cause problems because FDA rules allow too much variability across products. The standard bioequivalence range (80% to 125%) appears too broad for many ASMs, especially those exhibiting little separation between therapeutic and toxic levels. Hence, sub-therapeutic concentration may lead to therapeutic failure with seizure recurrence, which could be life threatening. A supra-therapeutic level could result in adverse effects or compliance issues. There is discussion in the epilepsy community about additional guidelines, including designation of generic ASMs as Narrow Therapeutic Index (NTI) drugs and how patient education plays a role in generic substitution.

This abstract describes key issues on generic substitution of antiseizure medications (ASMs).

A systematic literature review was conducted to examine outcomes associated with substitution of ASMs and to compare the different position statements of major epilepsy organizations.

The review outcomes show reported issues with generic substitutions of phenytoin, topiramate, levetiracetam, carbamazepine, and lamotrigine. Reported issues include serum concentration discrepancies, hospitalizations, injuries, breakthrough seizures, and loss of seizure control. The American Academy of Neurology (AAN) and the Epilepsy Foundation (EF) agree that generic substitutions should not be made without physician approval. Conversely, the American Epilepsy Society (AES) is in support of the FDA standards on bioequivalence of brand and generic ASMs.

Overall, based on the published evidence on specific generic ASMs, FDA bioequivalence standards are not the cause of problems with generic ASM substitution. Rather, it is imperative that physicians and pharmacists provide adequate patient education on what to expect when switching to generic ASMs, including changes in medication shape and color. Another suggestion would be to consider that all ASMs be considered for inclusion in NTI class to prevent the clinical outcome issues associated with generic ASM switching.