Abstracts

Rationale: In controlled experiments which attempt to determine the effect of intracranial brain stimulation (ICBS) in reducing or controlling seizures, the dosages of antiepileptic medications (AEDs) are kept constant by study design to minimize their influence as an alternate explanation for changes in seizure frequency. Previous epilepsy clinical trials have assumed therapeutic equivalence and therefore dosage stability when generic substitution has occurred during trials. Multiple recent studies have suggested that AED generic switching (brand to generic, generic to generic) may produce significant fluctuations in AED concentrations, resulting in an exacerbation of seizures or drug toxicity. Previous trials have not investigated the possible influence of generic substitution on the dependent variable. This study reviews the possible effects of generic substitution in a small cohort of patients closely monitored for changes in seizure frequency during a long term ICBS study. Methods: Patients enrolled in a FDA approved clinical trial to determine the safety and efficacy of ICBS for seizure control in the U.S. were identified. Patients were followed closely for changes in their antiepileptic therapy, including substitution of their original AED (brand or generic) for another generic AED formulation. Patients were seen every 3-6 months and details concerning seizure frequency and severity were provided in seizure diaries. Daily files of intracranial seizure data utilizing an implanted computer system with seizure detection software and implanted electrodes over the ictogenic zone were available for review and comparison to patient seizure diaries. Patients were extensively questioned about changes in lifestyle, medication regimen, medication adherence, and any other potential precipitating factors associated with seizures (menstrual periods, sleep deprivation, stress, concurrent illness, alcohol consumption) and AED toxicity (significant dietary change, drug interaction, change in dosing schedule). Results: Ten patients were identified who had long-term follow-up for seizure control including comprehensive seizure diaries and patient accounts of generic substitution and any changes which appeared to have occurred secondary to this change. Five patients reported increase in seizure frequency and/or severity within the month after formulation change of at least one AED, which did not appear secondary to changes in stimulation parameters or battery life. Four patients had no change in their AED formulations because of lack of available formulations, previous difficulty with switching formulations, or concern of risk in making the change. One patient switched to generic formulations without reported problems. Conclusions: Increased seizure frequency in 50% of patients in a small cohort closely monitored for changes in seizure frequency during a long term intracranial brain stimulation study suggests the need to investigate and/or control for the effect of generic substitution on the dependent variable in epilepsy clinical trials.