Table e-1 Geometric Mean Ratio 90% Confidence Limit of AUC(0-t)

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Table e-1 Geometric Mean Ratio 90% Confidence Limit of AUC(0-t) Carbamazepine 5 formulations 14 studies Divalproex 7 formulations Lamotrigine 17 studies Levetiracetam 15 formulations 41 studies Phenytoin 8 formulations 11 studies Total 42 formulations 97 studies 0%-5% 1 (7.14%) 2 (14.29%) 1 (5.88%) 23 (56.10%) 2 (18.18%) 29 (29.00%) 5%-10% 3 (21.43%) 8 (47.06%) 16 (39.02%) 5 (45.45%) 34 (35.05%) 10%-15% 8 (57.14%) 7(50.00%) 5 (29.41%) 1 (2.44%) 23 (23.71%) 15%-25% 3 (17.65%) 11 (11.34%) 14 (100.00%) 17 (100.00%) 41 (100.00%) 11(100.00%) 97 (100.00%) 90% CI includes 1 5 (35.71%) 13 (92.86%) 15 (88.23%) 36 (87.80%) 6 (54.54%) 75 (77.32%) Geometric Mean Ratio 90% Confidence Limit of Cmax Carbamazepine Divalproex Lamotrigine Levetiracetam Phenytoin Total 0%-5% 0 (0.00%) 1 (5.88%) 5 (12.20%) 6 (6.19%) 5%-10% 1 (7.14%) 4 (28.57%) 5 (29.41%) 19 (46.34%) 2 (18.18%) 31 (31.96%) 10%-15% 5 (37.71%) 5 (35.71%) 8 (47.06%) 12 (29.27%) 5 (45.45%) 35 (36.08%) 15%-25% 8 (57.14%) 3 (17.65%) 4 (36.36%) 25 (25.77%) 14 (100.00%) 17 (100.00%) 41 (100.00%) 11(100.00%) 97 (100.00%) 90% CI includes 1 3 (21.43%) 13 (76.47%) 18 (43.90%) 7 (63.63%) 49 (50.52%)

Figure e-1: Comparison of standard deviations of total drug exposure (AUC, figure 1A), and peak concentrations (Cmax, figure 1B) for generic and reference antiepilepsy drug formulations in bioequivalence studies. Standard deviations are presented in log scales. Abbreviations: PHT = phenytoin; CBZ = carbamazepine; DVP = divalproex; LEV = levetiracetam; LTG = lamotrigine. Cmax A AUC B

Figure e-2. Differences in fed and fasting bioequivalence (BE) studies. Tmax A AUC B Cmax C 2A: Fed and fasting studies of total drug exposure (AUC). 2B: Fed and fasting studies of maximum concentration (Cmax). 2C: Fed and fasting studies of time to maximum concentration (Tmax). Tmax had the largest food effects, with 60% of studies showing a >20% difference in Tmax between fed and fasting states.