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Ghost-Pill-Buster: A Case Study of Intact Levetiracetam Extended-Release Tablets after Dissolution Testing

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Abstract

Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgments

The authors would like to thank Drs. Lucinda Buhse, John Kauffman, John Peters, and Robert Lionberger for important insights and collaborations on this topic. Opinions expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the US Food and Drug Administration.

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Authors and Affiliations

  1. 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

    Dajun Sun, Hong Wen & Wenlei Jiang

  2. US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA

    Anna Externbrink, Zongming Gao & David Keire

  3. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

    Gregory Krauss

Authors
  1. Dajun Sun
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  2. Hong Wen
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  3. Anna Externbrink
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  4. Zongming Gao
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  5. David Keire
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  6. Gregory Krauss
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  7. Wenlei Jiang
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Corresponding author

Correspondence to Wenlei Jiang.

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Funding

No funding was specifically received for the conduct or publication of this study. 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 interagency agreement between the US Department of Energy and the US Food and Drug Administration.

Conflicts of interest

The authors—Dajun Sun, Hong Wen, Anna Externbrink, Zongming Gao, David Keire, Gregory Krauss, and Wenlei Jiang—declare that they have no conflicts of interest.

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Sun, D., Wen, H., Externbrink, A. et al. Ghost-Pill-Buster: A Case Study of Intact Levetiracetam Extended-Release Tablets after Dissolution Testing. CNS Drugs 30, 455–460 (2016). https://doi.org/10.1007/s40263-016-0332-9

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  • DOI: https://doi.org/10.1007/s40263-016-0332-9

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