EVALUATING FDA BIOEQUIVALENCE STANDARDS FOR GENERIC CARBAMAZEPINE FORMULATIONS [P05.085]

Kelly Chuang, Gregory L. Krauss, Ying J. Cao, Baltimore, MD

Many patients with epilepsy use generic formulations of brand name AEDs, including carbamazepine, lamotrigine, valproate, clobazam, and phenytoin. Although generics are licensed as “identical” or bioequivalent to their more expensive brand name counterparts, recent studies have questioned whether generic AEDs are truly interchangeable with branded medications or with one another for the treatment of epilepsy. These studies have highlighted several potential concerns with generic AEDs, including lower circulating drug levels, increased seizure rates or breakthrough seizures, high rates of switching back from generic to branded products, dose escalation, and the need for additional AEDs.^1-4

In this study, Chuang et al used pharmacokinetic data available from the FDA for branded carbamazepine and 5 generic carbamazepine formulations to examine whether the generic and branded carbamazepine formulations were truly bioequivalent. According to the FDA, bioequivalence between medications is examined using the area under the time-plasma concentration curve (area under curve [AUC]) and the maximum drug concentration in serum (C_max). Using the Freedom of Information Act, the investigators obtained FDA approval packets for the 5 generic carbamazepine formulations, and calculated 90% confidence intervals for the AUC and C_max values for each medication. For each drug, bioavailability data were assessed from a total of 4 studies—2 studies of a 200-mg dose and 2 studies of a 400-mg dose. For 3 of the 5 generic agents, the investigators concluded that the generic version was nearly identical to branded carbamazepine. For the remaining 2 generic formulations, the differences in AUC and C_max between the branded and generic carbamazepine products were close to the FDA’s limit of acceptability for bioequivalence. In addition, switching from one generic to another at the same dose level could produce changes in AUC by as much as 21% and variations of C_max of up to 40%. The investigators concluded that most generic carbamazepine formulations are accurate copies of branded carbamazepine, although there is a potential for significant shifts in circulating drug concentration with some generic products. The likelihood of a large change in drug levels is greatest when patients switch from one generic to another, and generic-to-generic switches may produce swings in concentration that exceed the bioequivalence limits established by the FDA. Although treatment efficacy was not evaluated in this study, the authors concluded that switching between generics should probably be avoided because these differences have the potential to expose patients to breakthrough seizure episodes or significant toxicity.⁵

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