Abstracts

Rationale: The FDA has recently proposed using more stringent evaluation, the Scaled Average Bioequivalence study, to establish bioequivalence for Narrow Therapeutic Index (NTI) Abbreviated New Drug Applications (ANDA) for generic medications. In this process, NTI drugs were defined as those drugs where small differences in dose or blood concentration may lead to dose and blood concentration dependent serious therapeutic failures or adverse drug reactions. Specific criteria included typical dose adjustments of less than 20% and therapeutic drug monitoring to ensure safe and effective use of the drug. This investigator initiated study evaluated several aspects of how the AED, lamotrigine, is used in standard clinical care in people with epilepsy to assess if it meets the proposed criteria for an NTI drug. Methods: We selected 10 sequential adult patients that were treated with lamotrigine for epilepsy for at least 18 months. Data collection started after the lamotrigine had been used for at least 6 months to avoid dose changes related to the initial titration. We determined the mean, median and standard deviation (SD) of each dose increment as a percent of the total daily dose of lamotrigine when it was adjusted to treat toxic adverse effects or seizures and the impact of therapeutic drug monitoring on dose adjustments in the course of standard treatment of epilepsy using a retrospective chart review. Results: Sixteen upward dose increments occurred during the observation period, median 12.5% (mean 16.7%; SD 11.1%). Eleven downward dose increments occurred, median 9.1% (mean 11.3%; SD 7.4%). All but 3 of these dose increments were equal to or less than 20% of the total daily dose. The 3 outliers occurred in one patient with a 50% and 33% upward and 33% downward increment. There were a total of 33 drug levels checked (range 1-8 per patient). After 16 of these levels the dose was adjusted. Conclusions: In standard clinical care of people with epilepsy, the median dose increment of lamotrigine, excluding the initial titration, was 11.1% of the total daily dose, which is well below the 20% bound proposed for NTI drugs. In addition, almost 60% (16/27) of these dose increments were preceded by a lamotrigine level. These results support classification of lamotrigine as an NTI drug. A larger, multicenter study, evaluating standard use of all of the AEDs that have pharmacokinetic characteristics consistent with a possible NTI drug classification, should be performed to inform the FDA's decision on identification of AEDs that fulfill the NTI drug criteria. Funding: None