title: Ghost-Pill-Buster: A Case Study of Intact Levetiracetam Extended-Release Tablets after Dissolution Testing.
abstract: Orally administered medications in extended-release (ER) dosage forms continue to play a pivotal role in the treatment of various central nervous system disorders. For certain ER dosage forms, pharmaceutical scientists have been familiar with the passage of intact tablet-like objects in patients' feces after administration of ER tablets or capsules based on water-insoluble or slowly dissolving excipients. Nevertheless, because of lack of awareness of the "ghost pill" phenomenon, anxiety has ensued among some patients and clinicians, who have less understanding of how drugs are released from these tablets once ingested. It has been brought to the attention of the US Food and Drug Administration (FDA) that epilepsy patients administered with Teva's levetiracetam ER tablets have noticed intact tablets in their stools and been concerned that they were not getting the needed dose of the drug. In response to neurologists' clinical reporting, the FDA has conducted investigations to confirm a minimal risk of incomplete drug release of Teva's drug product.
  
  
  
  The objective of this study was to evaluate the risks of incomplete drug release associated with the passing of intact levetiracetam ER tablets, by conducting in vitro dissolution testing.
  
  
  
  Dissolution testing of Teva's drug product was performed in accordance with the US Pharmacopeia monograph for levetiracetam ER tablets in phosphate buffer and bio-relevant buffers at different pH values. In addition, dissolution testing was conducted with split and crushed tablets. At the end of the dissolution testing, all samples were visually inspected for any undissolved pieces.
  
  
  
  Approximately 90 % of levetiracetam had been released in all dissolution media after 8 h of dissolution. The levetiracetam ER tablets after dissolution testing remained fully intact in all dissolution media. The rates of drug release were significantly faster from split and crushed tablets than that from whole tablets.
  
  
  
  On the basis of these findings, Teva's levetiracetam ER tablets may appear intact in the stools but have released the drug successfully. The FDA has requested Teva to revise its product labeling to include remarks regarding the potential passing of intact tablets. Since patients who notice ghost pills 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.
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Dajun
authors.initials: D
authors.lastname: Sun
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Externbrink
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA.
authors.forename: Zongming
authors.initials: Z
authors.lastname: Gao
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Keire
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Krauss
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA. wenlei.jiang@fda.hhs.gov.
authors.forename: Wenlei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000284:Administration, Oral; D002214:Capsules; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013607:Tablets; D014481:United States; D014486:United States Food and Drug Administration / Q000331:legislation & jurisprudence
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D013607:Tablets; D000077287:Levetiracetam; D010889:Piracetam