Objectives: This is an evidence report prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center examining the comparative efficacy, safety, and tolerability of newer versus older and innovator versus generic antiepileptic medications.
Data Sources: MEDLINE (starting from 1950), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews, and Web of Science from the earliest possible date through March 23, 2011.
Review Methods: Controlled clinical trials and controlled observational studies were included in our comparative effectiveness review if they met the following inclusion criteria: compared older to newer antiepileptic medications or innovator to generic antiepileptic medications, conducted in patients with epilepsy, and reported data on prespecified clinical or humanistic outcomes. Using predefined criteria, data on study design, interventions, quality criteria, study population, baseline characteristics, and outcomes were extracted. All of the available data was qualitatively evaluated and where possible, statistically pooled. For dichotomous endpoints, we used relative risks, and for continuous endpoints, we used weighted mean differences or standardized mean differences. Both were calculated using a DerSimonian and Laird random effects model and reported with 95 percent confidence intervals. When mean change scores from baseline for each group were not reported, the difference between the mean baseline and mean followup scores for each group and the standard deviations of the change scores were calculated. I2 was used to detect statistical heterogeneity and Egger's weighted regression statistics were used to assess for publication bias. The strength of the body of evidence for each outcome was rated as insufficient, low, moderate, or high.
Results: Patients given newer antiepileptic medications were less likely to be seizure free for 6–12 months or 24 months and had a greater risk of withdrawing due to a lack of efficacy than those receiving carbamazepine. The risk of withdrawing due to adverse events and the risk of several adverse events including fatigue, somnolence, dizziness, and skin rash were significantly reduced when patients received newer antieplipetic medications versus carbamezepine, but the risk of withdrawing for any reason was not significantly impacted. Similarly, patients receiving newer antiepileptic medications were more likely to withdraw due to a lack of efficacy than those receiving carbamazepine sustained or controlled release products but are more likely to withdraw due to adverse events and skin rash. The risk of withdrawing for any reason was not significantly impacted.
There was no significant difference in the risk of being seizure free for the study duration when newer antiepileptic medications were compared against phenytoin or valproic acid, or the risk of being seizure free at 6–12 or 24 months for valproic acid. No significant differences were seen for newer antiepileptic medications versus either phenytoin or valproic acid for withdrawals for any reason, withdrawals due to lack of efficacy, or withdrawals due to adverse events. The risk of certain adverse events including fatigue, somnolence, nausea, and alopecia were significantly lower for newer antiepileptic medications versus valproic acid. The risks of vomiting and gum hyperplasia were significantly lower for newer antiepileptic medications versus phenytoin. For the comparison of innovator antiepileptic medications to their respective generic versions, we found that seizure occurrence, seizure frequency, total withdrawals, withdrawals due to lack of efficacy, or withdrawals due to adverse events were not significantly different in controlled clinical trials. Using data from observational studies, switching from an innovator to a generic antiepileptic medication may increase the risk of hospitalization, hospital stay duration, and the composite of medical service utilization but may not increase outpatient service utilization.
Conclusions: Carbamazepine had advantages in epilepsy control over newer antiepileptic medications as a class but had more adverse effects. Valproic acid and phenytoin provided epilepsy control similar to newer antiepileptic medications, but there were adverse events that occurred more commonly with these older antiepileptic medications. However, these adverse events did not significantly increase the risk of withdrawals.
In patients who need to initiate an antiepileptic medication, we could find no substantive differences in terms of benefits or harms associated with the use of an innovator versus a generic. There was insufficient to low strength of evidence suggesting that switching from an innovator to a generic, generic to generic, or generic to innovator version of the same medication may increase the short-term risk of hospitalization and hospital stay duration and may increase the short-term risk of a composite of having an emergency department and hospitalization visit with or without ambulance service utilization.