Agency for Healthcare Research and Quality
Effectiveness and Safety of Antiepileptic Medications in Patients With Epilepsy
Executive Summary Dec. 21, 2011
Overview of Key Findings
Our evaluation of newer versus older antiepileptic medications was predominantly limited to newer antiepileptic medication comparisons versus carbamazepine, valproic acid, and to a lesser extent phenytoin. Carbamazepine had advantages in epilepsy control over the newer antiepileptic medications it was compared with but had more adverse effects. The risk of withdrawing due to lack of efficacy was decreased, and withdrawing due to adverse events was increased, leading to a neutral effect on withdrawing for any reason. Valproic acid and phenytoin provided similar epilepsy control to newer antiepileptic medications, although newer antiepileptic medications had a longer time to first seizure versus phenytoin. While the risk of withdrawing due to adverse events was not significantly different with valproic acid or phenytoin versus newer antiepileptic medications, there were adverse events that occurred more commonly with these older antiepileptic medications. So, when qualitatively assessing the balance of benefits to harms, carbamazepine offers similar comparative effectiveness versus newer antiepileptic medications with greater benefit but more harms. Newer antiepileptic medications may have some advantages over valproic acid and phenytoin in comparative effectiveness with similar benefits but less harms.
In a patient who needs to initiate an antiepileptic medication, we could find no substantive differences in terms of benefits or harms associated with the use of a generic version versus an innovator product. Our data is limited predominantly to innovator versus generic versions of carbamazepine and to a lesser extent phenytoin and valproic acid. We could find no substantive differences in pharmacokinetic parameters between generic and innovator versions of the same antiepileptic medication either. While the source of the innovator and the generic (internationally versus domestically) may impact the variability in blood concentrations, the pharmacokinetic and final health outcomes results for initiating innovator versus generic medications seem congruent. In our literature set, patients were studied in a crossover or parallel design so when they were allocated to therapy or switched between therapies, the tendency for loss of efficacy or harm associated with switching might be similarly distributed across the groups. As such, this data cannot prove that intermediate or final health outcomes would be similar for the short-term period (several days to weeks) after an innovator or generic product is switched to another version of the medication versus maintaining the patient on their previous therapy. Switching from an innovator to a generic antiepileptic medication may increase the risk of hospitalization and hospital stay duration and may increase the risk of a composite of having an emergency department and hospitalization visit with or without ambulance service utilization. However, this is based on controlled observational study data, which has inherent limitations substantially reducing the strength of evidence. In addition, this data cannot be used to say that use of generic antiepileptic medications are less efficacious or safe than innovator versions for long-term therapy.
Only one outcome, the risk of gum hyperplasia with phenytoin versus newer antiepileptic medications, had a high strength of evidence. For the outcomes reported in the executive summary, the strength of evidence was predominantly moderate to low for the newer versus older antiepileptic medication evaluation and low to insufficient for the innovator versus generic evaluation. In many cases, strength of evidence was reduced for issues of inconsistency and imprecision. Pooling multiple newer antiepileptic medication comparisons versus a single older antiepileptic medication enhanced power to detect differences but reduced consistency. Precision frequently was impacted negatively by having only a few small trials for an analysis. Analyses with only observational studies had a greater risk of bias which negatively impacted strength of evidence.
Applicability of evidence for both the newer versus older antiepileptic medication evaluation and the innovator versus generic evaluation was more evenly dispersed between insufficient, low, and moderate with no areas of high applicability. For the innovator versus generic evaluations, the lack of specification that the products were A rated generics and the multitude of studies conducted outside the United States limited applicability.