Abstracts

Rationale: FDA is now recommending a bioequivalence (BE) approach for NTI drugs with a four-way, fully replicated, crossover study design that permits the simultaneous equivalence comparison of the mean and within-subject variability between the test and reference products as described in the draft guidance for warfarin sodium tablets. To address the public concerns about therapeutic equivalence and generic substitution of AED drugs, FDA conducted comprehensive evaluation on a list of AED products against the critical characteristics of NTI drugs.Methods: We reviewed data from the drug product label, literature, as well as relevant new drug applications (NDAs) and abbreviated new drug applications (ANDAs), for a list of AED products, including lamotrigine, carbamazepine, phenytoin, levetiracetam, topiramate, and valproic acid. We evaluated these drugs against the following characteristics of NTI drugs: (1) whether there is little separation between minimal therapeutic and toxic blood concentrations, (2) whether sub-optimal concentrations or doses lead to serious therapeutic failures or adverse events, (3) whether therapeutic drug monitoring (TDM) is recommended, (4) whether the within-subject variability is low-to-moderate (i.e. CV is less than 30%), and (5) whether dose is often adjusted in very small increments in the maintenance stage (such as less than 20%) in clinical practice.Results: Generally, sub-therapeutic concentrations of these AED drugs increased the risk of uncontrolled seizure. However, the ratio of minimal toxic and effective concentration of lamotrigine (i.e., 10) was much higher than those of carbamazepine, phenytoin and valproic acid (i.e., 2~3). Levetiracetam and topiramate did not have an established therapeutic range, and toxic/therapeutic concentration ratio could not be determined. Levetiracetam had a relatively low order of toxicity and a relatively high therapeutic index. Additionally, lamotrigine, levetiracetam, and topiramate were not subject to routine TDM, while the other three were. All investigated AEDs had small to moderate within-subject variability. Sufficient clinical practice data were not available to evaluate dose adjustment, but small dose adjustment was anticipated for carbamazepine, phenytoin and valproic acid.Conclusions: Based on currently available data, we concluded that there is variation within the AED class with respect to the properties related to their therapeutic index and that each drug needs to be evaluated individually (Table 1).