Abstracts

Rationale: Epileptic patients are often treated with extended-release (ER) oral dosage forms of anti-epileptic drugs for convenience and to improve treatment adherence. For certain ER dosage forms, the passage of intact tablet-like objects in patients' feces may be observed in patients after administering ER tablets based on water-insoluble or slowly dissolving excipients. Some epilepsy patients administered with Teva's generic levetiracetam ER tablets noticed intact tablets in their stools and were concerned that they were not getting the needed dose of the drug. In response to neurologists' clinical reporting, this study aims to evaluate the risks of incomplete drug release associated with the passing of intact Teva's levetiracetam ER tablets by conducting in vitro dissolution testing in order to confirm a minimal risk of incomplete drug release. Methods: Dissolution experiments using the United States Pharmacopeia (USP)-recommended method for levetiracetam ER tablets were conducted to compare the drug release profiles of Teva's levetiracetam ER product in phosphate buffer and those in simulated gastric fluid (SGF), fasted-state and fed-state intestinal fluid (FaSSIF, FeSSIF). In addition, dissolution testing was conducted with split and crushed tablets. At the end of dissolution testing, all samples were visually inspected for any undissolved pieces. Results: Approximately 90% of levetiracetam had been released in all dissolution media after eight hours of dissolution (Figure 1). The levetiracetam ER tablets after dissolution testing remained fully intact in all dissolution media (Figure 1 inset). The rates of drug release were significantly faster from split and crushed tablets than that from whole tablets. Conclusions: Our dissolution studies showed that Teva's levetiracetam ER formulation may remain intact after dissolution; however, the levetiracetam was released successfully. Food and Drug Administration (FDA) has requested Teva to revise its product labeling to include remarks regarding the potential passing of intact tablets. Since patients who notice ghost tablets in their stools may impetuously crush or split the tablets of subsequent doses on their own, healthcare providers should instruct patients to swallow whole tablets throughout the treatment in accordance with the drug label. In the meantime, the FDA strives to ensure that labeling of generic drug products is consistent with complete and updated information pertinent to usage. If the clinical observations are inconsistent with drug labels, patients and clinicians are encouraged to report any passing intact medications via the FDA Adverse Event Reporting System (FAERS) as part of ongoing surveillance efforts. Funding: Anna Externbrink was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.