Abstracts

ABSTRACT WITHDRAWN
Rationale: The FDA defines a generic drug as being “identical, or bioequivalent to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use.” Physicians and patients with epilepsy, however, are often concerned that FDA bioequivalence standards for generic antiepilepsy drugs (AEDs) may not be adequate to prevent seizures or side-effects following formulation switches. We used carbamazepine bioequivalence data to examine FDA claims that: 1) generic AEDs are accurate copies of brand-name formulations; 2) brand-name formulations may be variable and provide no increased benefit over generic AEDs; 3) switches between generic formulations are safe. Methods: We obtained FDA approval packets for five generic carbamazepine formulations using the Freedom of Information Act. We compared average bioequivalence measurements (90% C.I. for AUC and Cmax ratios) for generic formulations and Tegretol. We assessed the variability of Tegretol (Cmax and AUC) across the bioequivalence studies. Finally, using Tegretol as an index for 3 studies using 400 mg test doses, we determined likely changes in carbamazepine concentration following switches between generic formulations. Results: Three of five generic formulations were accurate copies of Tegretol, however, AUC and Cmax were near the acceptance range for one formulation. TABLE. Tegretol concentrations vary markedly across bioequivalence studies--mean AUC varied up to 37%; average Cmax varied up to 17%. Using Tegretol as an index, three possible switches between three generic formulations would produce variations in AUC of up to 34%: 90% CI (1.19, 1.34); (1.13, 1.31); and (0.97, 1.11) and up to 51% variations in Cmax: 90%C.I. of (0.99, 1.21), (1.31, 1.51) and (0.7, 0.87). Conclusions: Most generic carbamazepine formulations are accurate copies of Tegretol, however, one formulation provides concentrations near the acceptance limits. Tegretol bioavailability varies markedly across bioequivalence studies and may provide no significant benefits compared to some generic formulations. Switches between generic carbamazepine formulations are likely to produce large concentration shifts which are outside FDA bioequivalence acceptance ranges, suggesting that switches between generic carbamazepine formulations should be avoided.