Clinical problems with generic antiepileptic drugs - Comparison of sustained-release formulations of carbamazepine

Objective: In the treatment of epilepsy, as in all areas of drug therapy, g eneric formulations are becoming more important as pressure to reduce drug costs increases. In clinical practice, the interchangeability of reference and generic preparations is often assumed. However, in individual patients with a narrow therapeutic range, switching to another formulation of an ant iepileptic agent with law water solubility and nonlinear pharmacokinetics m ay lead to breakthrough seizures or toxicity. The purpose of this study was to examine the bioequivalence and clinical effects after switch of equal d aily dosages of two commercially available sustained-release preparations o f carbamazepine (CBZ). Patients and Study Design: This was a nonblinded intra-individual trial in 14 patients aged 18 to 52 years with focal epilepsy who had been receiving monotherapy with the reference preparation of sustained-release carbamazepi ne (mean dosage 1985 mg/day given twice daily) for at least 35 days. After a minimum of 3 further days, the reference preparation (denoted CBZ-R) was immediately replaced by an identical dosage of the generic preparation (den oted CBZ-G). Under steady-state conditions, for each preparation we determi ned area under the serum concentration-time curve (AUC), maximum serum conc entration (C-max), minimum serum concentration (C-min) and peak-trough fluc tuation (PTF) of carbamazepine and carbamazepine 10,11-epoxide. Results: One patient dropped out because of intolerable adverse effects wit h CBZ-G. For carbamazepine, the data for the remaining 13 patients, express ed as CBZ-G/CBZ-R, were: AUC 111.5% [90% confidence interval (CI) 105.6-117 .8%]; PTF 90.9% (90% CI73.4-112.8%); C-max 110.1% (90% CI 100.4-117.0%). Th ese data indicate a higher bioavailability for CBZ-G. For carbamazepine 10, 11-epoxide, about 20% higher average concentrations were measured with CBZ- G. Applying the usual inclusion rule [90% CI within the range 80 to 125% (A UC) or 70 to 143% (PTF and C-max) of the reference preparation], the two fo rmulations can be considered as bioequivalent. In contrast, we observed mar ked adverse effects, such as dizziness, nausea, ataxia, diplopia and nystag mus, in eight of the remaining 13 patients after switching to CBZ-G. Conclusions: Proof of bioequivalence between reference and generic preparat ions of antiepileptic drugs does not mean that they are freely interchangea ble. Generic formulations with proven bioequivalence to branded preparation s can be used, for example, at the beginning of treatment or in poorly cont rolled patients with serum concentrations in the mid range. The results dem onstrate that the usual rules for bioequivalence and the range of acceptabi lity for preparations of carbamazepine are problematic.