July 8, 2011 â€” Switching between different generic versions of antiepileptic drugs (AEDs) may cause greater changes in plasma drug concentrations compared with making a generic substitution of a brand-name product, a new study indicates.
“Clinicians should be aware that most generic anticonvulsants are probably safe to prescribe for their patients,” lead investigator Gregory Krauss, MD, from the Department of Neurology, Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News.
However, they should consider asking patients and their pharmacists to minimize switches between various generic formulations, since they potentially could produce large swings in drug blood levels,” Dr. Krauss advises.
The study was published online June 29 in the Annals of Neurology.
In the past several years, the US Food and Drug Administration (FDA) has approved more than 150 generic AED formulations, substantially reducing the cost of treating epilepsy.
The FDA grants approval for generics through an Abbreviated New Drug Application (ANDA) when it has been demonstrated (in healthy volunteers) that the generic drug provides plasma concentrations similar to those of corresponding reference (brand-name) formulations.
This is established in small bioequivalence studies in which peak concentrations (Cmax) and total drug exposure over time (AUC) of the generic AED are compared with those of the brand-name version. The generic currently has to meet a bioequivalence standard of 80% to 125%.
To compare how generic AEDs stack up to their brand-name counterparts, as well as other generic formulations of the same drug, Dr. Krauss and colleagues assessed bioequivalence data for 141 generic AEDs.
They found that AUC values for generic and brand-name formulations were “very similar in nearly all bioequivalence studies,” with mean AUC values differing by less than 10% in 83% of the studies and by more than 15% in only 1 study.
Mean Cmax values between generic and brand-name products differed by less than 15% in 89% of studies and by 15% to 25% in 11% of studies.
“Intersubject variability in Cmax and AUC was small and similar for reference and generic products,” the investigators write.
However, in simulated generic-to-generic switches between 595 pairs of generic AED formulations, estimated AUC differed by more than 15% for 17% of pairs and estimated Cmax differed by more than 15% for 39% of pairs. AEDs with low bioavailability and solubility, such as oxcarbazepine, demonstrated the greatest variability in bioequivalence.
To put the findings in perspective, Dr. Krauss said “2 generic products could provide levels +15% and -15% of the brand name, with a 30% swing in a switch between the generics.”
Although these estimates need to be confirmed, they do suggest that some generic-to-generic product switches “could potentially produce large differences in PK [pharmacokinetics] than brand-name to generic product substitutions,” the investigators caution.
Overall, they say their analysis confirms equivalent total exposure of generic AEDs to relative reference formulations and demonstrates “potential novel findings on generic-to-generic switches.”
“It would be helpful to study generic absorption in actual patients and also in special groups such as the elderly and children, rather than only in paid volunteers,” Dr. Krauss told Medscape Medical News.
He also said the FDA “might want to consider classifying antiepilepsy drugs as ‘critical dose’ drugs and pick narrower acceptance limits in the bioequivalence tests comparing generic and brand name formulations.”
In April 2010, the FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee did discuss designating “critical dose drugs” that must meet a narrower standard for AUC.
At the meeting, the committee agreed that critical dose drugs are a distinct group of drugs and that the FDA should develop a list of them. The committee further agreed that the current bioequivalence standards are not sufficient for critical dose drugs and indicated a need for more rigorous standards.
Dr. Krauss and his colleagues point out that in Denmark, AEDs other than benzodiazepines are designated “narrow therapeutic index” drugs and generic formulations must meet a 90% to 111% bioequivalence standard, as opposed to the current US standard of 80% to 125%.
This tighter standard would have been met for AUC by 81% of the bioequivalence studies in the current analysis and for Cmax by 64% of studies, Dr. Krauss and colleagues note.
The study was supported by a grant from the National Center for Research Resources, part of the National Institutes of Health. Dr. Krauss has disclosed financial relationships with UCB Pharma, Eisai Laboratories, and Icagen Pharmaceuticals.
Ann Neurol. Published online June 29, 2011