COMMENTARY—Study Reaffirms FDA Findings

The study by Dr. Kesselheim and his colleagues is one of several recently aimed at reviewing the overall safety of generic drug switching. The FDA sponsored three clinical bioequivalence studies to determine the adequacy of average bioequivalence studies for ensuring safe conversion between different antiseizure products for patients with epilepsy. Taken together, these studies confirm that most patients can safely switch between generic formulations, even between tablets differing in appearance.

So why do patients and open series report seizures associated with formulation changes? Probably several things are happening:

• Patients want to find a reason for the near-random pattern of their seizures. Threshold cortical epileptogenic activity triggers seizures in near-random patterns, and their timing might be influenced by triggers such as missing doses, stress, and hormonal changes.

• Patients’ views of illness and treatments might influence their reporting of seizures and drug effects. This search for seizure explanations can even extend to pets with seizures.

• There is temporal variability in individual drug absorption and elimination. Food has a major effect on absorption of antiseizure medications and maximum concentration; this effect is particularly common with modified-release formulations. A small subgroup of patients in the FDA’s clinical bioequivalence studies had variability in concentrations during reexposure to the same product.

• A small group of patients may be outside the 90% confidence interval bioequivalence acceptance range and may experience product switching effects.

—Gregory L. Krauss, MD
Professor of Neurology
Johns Hopkins University, Baltimore

—Michael D. Privitera, MD
Professor of Neurology
University of Cincinnati

This commentary was adapted from Krauss GL, Privitera M. More data on the safety of generic substitution: yes, the blue tablet is OK? Neurology. 2016 Sep 28 [Epub ahead of print].