CNS Drugs

, Volume 28, Issue 1, pp 69–77 | Cite as

Generic Products of Antiepileptic Drugs: A Perspective on Bioequivalence, Bioavailability, and Formulation Switches Using Monte Carlo Simulations

  • Vangelis Karalis
  • Panos Macheras
  • Meir Bialer
Original Research Article



Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics.


The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products.


Monte Carlo simulations of the classic 2 × 2 BE studies were performed to study the effect of sample size, within-subject variability, and the true difference in pharmacokinetic values of the products under comparison on BE acceptance of generic AED products. Simulations were extended to study the comparative performance of two generic AED products against the same innovative product. The simulated results are compared with literature data on AEDs.


The question with regard to bioavailability (BA) is whether two formulations are different, while for BE the question is whether two formulations are sufficiently similar in terms of extent and rate of absorption. Therefore, the criteria for BA and BE and the statistical analysis involved in their analysis are different. Two generic formulations that meet regulatory approval requirements for generics by being bioequivalent to the same innovative AED may not be bioequivalent to one another and therefore should not be regarded as equal or as therapeutically equivalent products. A switch from a standard or an immediate-release formulation to a modified-release product, which comprises extended-release or delayed-release formulations, should not be regarded as a switch between generics, but rather as a switch between different formulation types.


Switches between bioequivalent generic AED products could potentially lead to larger changes in plasma levels and exposure than the brand-to-generic switch. The simulation work verified the clinical findings that not all generic AED products bioequivalent to the same innovative product are bioequivalent to one another.


Two generic formulations that meet regulatory approval requirements for generics, by being bioequivalent to the innovative AED, may not be bioequivalent to one another. Additional BE criteria are needed for a formulation switch, particularly in epilepsy, where a breakthrough seizure may change a patient’s status from seizure-free to refractory.


Drug Product Reference Product Geometric Mean Ratio Generic Drug Product Breakthrough Seizure 
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The authors confirm that they have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflict of interest

The study was not supported by any funding. Dr. Meir Bialer has received in the last 3 years speakers or consultancy fees from Bial, CTS Chemicals, Desitin, Janssen-Cilag, Rekah, UCB Pharma and Upsher-Smith and has been involved in the design and development of new antiepileptics and CNS drugs as well as new formulations of existing drugs. None of the other authors have any conflict of interest to disclose.


  1. 1.
    Davit BM, Nakama PE, Buehle GJ, Conner DP, Haidar SH, Patel DT, Yang Y, Yu LX, Woodcock J. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United State Food and Drug Administration. Ann Pharmacother. 2009;43:1583–97.PubMedCrossRefGoogle Scholar
  2. 2.
    Verbeeck RK, Musuamba FT. The revised 2010 EMA guideline for the investigation of bioequivalence for immediate release oral formulations with systemic action. J Pharm Pharm Sci. 2012;15:376–99.PubMedGoogle Scholar
  3. 3.
    EMA (European Medicines Agency). Evaluation of medicines for human use, CHMP. Guideline on the investigation of bioequivalence. London. 2010.Google Scholar
  4. 4.
    Bialer M. Generic products of antiepileptic drugs (AEDs): is it an issue? Epilepsia. 2007;48:1825–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Bialer M, Midha KK. Generic products of antiepileptic drugs (AEDs): a perspective on bioequivalence and interchangeability. Epilepsia. 2010;51:941–50.PubMedCrossRefGoogle Scholar
  6. 6.
    Gange JJ, Avron J, Shrank WH, Schneeweiss S. Refilling and switching of antiepileptic drugs and seizure-related events. Clin Pharmacol Ther. 2010;88:347–53.CrossRefGoogle Scholar
  7. 7.
    Kesselheim AS, Stedman MR, Bubrick EJ, Gange JJ, Misono AS, Lee JL, Brookhart MA, Avron J, Shrank WH. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs. 2010;70:605–21.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Moore N, Barndi D, Beguad B. Are generic drugs really inferior medicines? Clin Pharmacol Ther. 2010;88:302–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Berg MJ. What’s the problem with generic antiepileptic drugs? Neurology. 2007;68:1245–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Berg MJ, Gross RA, Haskins LS, Zingaro WM, Tomaszewski KJ. Generic substitution in the treatment of epilepsy: patient and physician perception. Epilepsy Behav. 2008;13:693–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Berg MJ, Gross RA, Tomaszewski KJ, Zingaro WM, Haskins LS. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology. 2008;71:525–30.PubMedCrossRefGoogle Scholar
  12. 12.
    FDA (Food and Drug Administration). Report, Information regarding antiepileptic drugs. US Food and Drug Administration in response to request in Senate Report no. 111-39 and House Agriculture Committee Report No. 111-279. 2011.Google Scholar
  13. 13.
    Jobst BC, Holmes GL. Prescribing antiepileptic drugs: should patients be switched on the basis of cost? CNS Drugs. 2004;18:617–28.PubMedCrossRefGoogle Scholar
  14. 14.
    EMA (European Medicines Agency). Evaluation of Medicines for Human Use, CPMP. Note for guidance on the investigation of bioavailability and bioequivalence. London. 2001.Google Scholar
  15. 15.
    FDA (Food and Drug Administration). Center for Drug Evaluation and Research (CDER), bioavailability and bioequivalence studies for orally administered drug products, general considerations. Rockville, MD. 2003.Google Scholar
  16. 16.
    Bois FY, Tozer TN, Hauck WW, Chen ML, Patnaik R, Williams RL. Bioequivalence: performance of several measures of extent of absorption. Pharm Res. 1993;11:715–22.CrossRefGoogle Scholar
  17. 17.
    Bois FY, Tozer TN, Hauck WW, Chen ML, Patnaik R, Williams RL. Bioequivalence: performance of several measures of rate of absorption. Pharm Res. 1994;11:966–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Chen ML, Lesko LJ, Williams RL. Measures of exposure versus measures of rate and extent of absorption. Clin Pharmacokinet. 2001;40:565–72.PubMedCrossRefGoogle Scholar
  19. 19.
    FDA (Food and Drug Administration). Process for approving generic drugs. October 29, 2002. Available at: Accessed 28 Jan 2009.
  20. 20.
    Haidar S, Davit B, Chen ML, Conner D, Lee L, Li Q, Lionberger R, Makhlouf F, Patel D, Schuirmann D, Yu L. Bioequivalence approaches for highly variable drugs and drug products. Pharm Res. 2008;25:237–41.PubMedCrossRefGoogle Scholar
  21. 21.
    Haidar S, Makhlouf F, Schuirmann D, Hyslop T, Davit B, Conner D, Yu L. Evaluation of a scaling approach for the bioequivalence of highly variable drugs. AAPS J. 2008;10:450–4.PubMedCrossRefGoogle Scholar
  22. 22.
    FDA (Food and Drug Administration). Office of generic drugs, draft guidance for industry on bioequivalence recommendations for progesterone capsules. 2011.Google Scholar
  23. 23.
    FDA (Food and Drug Administration). Meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 2011 (Briefing information).Google Scholar
  24. 24.
    FDA (Food and Drug Administration). Draft guidance on warfarin sodium. 2012.Google Scholar
  25. 25.
    FDA (Food and Drug Administration). Draft guidance on tacrolimus capsule oral. 2012.Google Scholar
  26. 26.
    Anderson S, Hauck WW. The transitivity of bioequivalence testing: potential for drift. Int J Clin Pharmacol Ther. 1996;34:369–74.PubMedGoogle Scholar
  27. 27.
    Olling M, Mensinga TT, Barends DM, Groen C, Lake OA, Meulenbelt J. Bioavailability of carbamazepine from four different products and the occurrence of side effects. Biopharm Drug Dispos. 1999;20:19–28.PubMedCrossRefGoogle Scholar
  28. 28.
    Tothfalusi L, Speidl S, Endrenyi L. Exposure-response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets. Br J Clin Pharmacol. 2008;65:110–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Tothfalusi L, Endrenyi L. Approvable generic carbamazepine formulations may not be bioequivalent in target patient populations. Int J Clin Pharmacol Ther. 2013;51:525–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Maliepaard M, Banishki N, Gispen-de Wied CC, Teerenstra S, Elferink AJ. Interchangeability of generic anti-epileptic drugs: a quantitative analysis of topiramate and gabapentin. Eur J Clin Pharmacol. 2011;67:1007–16.Google Scholar
  31. 31.
    Rowland M, Tozer T. N. Clinical pharmacokinetics and pharmacodynamics. 4th ed. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia. 2011.Google Scholar
  32. 32.
    Hottinger M, Liang BA. Deficiencies of the FDA in evaluating generic formulations: addressing narrow therapeutic index dugs. Am J Law Med. 2012;38:667–89.Google Scholar
  33. 33.
    Schuirmann D. A comparison of the two one-sided tests procedure and the power approach for assessing equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;18:657–80.CrossRefGoogle Scholar
  34. 34.
    Midha K, Rawson M, Hubbard J. Bioequivalence: switchability and scaling. Eur J Pharm Sci. 1998;6:87–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Tothfalusi L, Endrenyi L, Midha KK, Rawson MJ, Hubbard JW. Evaluation of the bioequivalence of highly-variable drugs and drug products. Pharm Res. 2001;18:728–33.PubMedCrossRefGoogle Scholar
  36. 36.
    Tothfalusi L, Endrenyi L. Limits for the scaled average bioequivalence of highly variable drugs and drug products. Pharm Res. 2003;20:382–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Karalis V, Symillides M, Macheras P. Novel scaled average bioequivalence limits based on GMR and variability considerations. Pharm Res. 2004;21:1933–42.PubMedCrossRefGoogle Scholar
  38. 38.
    Karalis V, Symillides M, Macheras P. On the leveling-off properties of the new bioequivalence limits for highly variable drugs of the EMA guideline. Eur J Pharm Sci. 2011;44:497–505.PubMedCrossRefGoogle Scholar
  39. 39.
    Karalis V, Symillides M, Macheras P. Bioequivalence of highly variable drugs: a comparison of the newly proposed regulatory approaches by FDA and EMA. Pharm Res. 2012;29:1066–77.PubMedCrossRefGoogle Scholar
  40. 40.
    Nightingale SL, Morrison JC. Generic drugs and prescribing physician. JAMA. 1987;258:1200–4.PubMedCrossRefGoogle Scholar
  41. 41.
    Benet L, Goyan JE. Bioequivalence and narrow therapeutic index drugs. Pharmacotherapy. 1995;15:433–40.PubMedGoogle Scholar
  42. 42.
    Henney J. Review of generic bioequivalence studies. JAMA. 1999;282:1995.Google Scholar
  43. 43.
    Nightingale S. Therapeutic equivalence of generic drugs: letter to health practitioners. 2001. Available at: Accessed 1 May 2009.
  44. 44.
    Privitera M. Generic antiepileptic drugs: current controversies and future directions. Epilepsy Curr. 2008;8:113–7.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Chen M-L, Shah V, Ganes D, Midha KK, Caro J, Nambiar P, Rocci M Jr, Avinash G, Abrahmsson B, Conner D, David B, Fackler P, Farrel C, Gupta S, Katz R, Metha M, Preskorn SH, Sanderink G, Stavchansky S, Temple R, Wang W, Winkle H, Yu L. Challenges and opportunities in establishing scientific and regulatory standards for determining therapeutic equivalence of modified-release products: workshop summary report. Clin Ther. 2010;32:1704–12.PubMedCrossRefGoogle Scholar
  46. 46.
    Bialer M. Extended release formulations for the treatment of epilepsy. CNS Drugs. 2007;21:765–74.PubMedCrossRefGoogle Scholar
  47. 47.
    Diletti E, Hauschke D, Steinijans VW. Sample size determination for bioequivalence assessment by means of confidence intervals. Int J Clin Pharmacol Ther Toxicol. 1991;29:1–8.PubMedGoogle Scholar
  48. 48.
    Diletti E, Hauschke D, Steinijans VW. Sample size determination: extended tables for the multiplicative model and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43. Int J Clin Pharmacol Ther Toxicol. 1992;30:287–90.PubMedGoogle Scholar
  49. 49.
    Wolf P. Political campaign in Denmark. In: Abstract book from the 27th International Epilepsy Congress in Singapore, 2007. 8th–12th July 2007, p. 8–9.Google Scholar
  50. 50.
    Wolf P. Should newly diagnosed epilepsy be treated with generics? Nat Clin Pract. 2008;4:176–7.CrossRefGoogle Scholar
  51. 51.
    Johannessen SI, Batino D, Berry DJ, Bialer M, Kramer G, Tomson T, Patsalos P. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther. Drug Monit. 2003;25:347–63.PubMedCrossRefGoogle Scholar
  52. 52.
    Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E. Antiepileptic drugs—best practice guidance for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring. ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49:1239–76.Google Scholar
  53. 53.
    Bialer M, Levy RH, Perucca E. Does carbamazepine have a narrow therapeutic plasma concentration range? Ther Drug Monit. 1998;20:56–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Advagraf: Summary of Product Characteristics (SmPC).
  55. 55.
    Trinka E, Krämer G, Graf M. Requirements for generic antiepileptic medicines: a clinical perspective. J Neurol. 2011;258:2128–32.PubMedCrossRefGoogle Scholar
  56. 56.
    Sander JW, Ryvlin P, Stefan H, Booth DR, Bauer J. Generic substitution of antiepileptic drugs. Expert Rev Neurother. 2010;10:1887–98.PubMedCrossRefGoogle Scholar
  57. 57.
    Bialer M, Shekh-Ahmed T, Braun T, Halvorsen MB. Comparative steady-state pharmacokinetic evaluation of immediate-release topiramate and USL255, a once-daily extended-release topiramate formulation. Epilepsia. 2013;54:1444–52.PubMedCrossRefGoogle Scholar
  58. 58.
    García-Arieta A. The failure to show bioequivalence is not evidence against generics. Br J Clin Pharmacol. 2010;70:452–3.Google Scholar
  59. 59.
    Gwaza L, Gordon J, Welink J, Potthast H, Hansson H, Stahl M, García-Arieta A. Statistical approaches to indirectly compare bioequivalence between generics: a comparison of methodologies employing artemether/lumefantrine 20/120 mg tablets as prequalified by WHO. Eur J Clin Pharmacol. 2012;68:1611–8.Google Scholar
  60. 60.
    Herranz M, Morales-Alcelay S, Corredera-Hernández MT, de la Torre-Alvarado JM, Blázquez-Pérez A, Suárez-Gea ML, Alvarez C, García-Arieta A. Bioequivalence between generic tacrolimus products marketed in Spain by adjusted indirect comparison. Eur J Clin Pharmacol. 2013;69:1157–62.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Laboratory of Biopharmaceutics & Pharmacokinetics, Faculty of PharmacyNational & Kapodistrian University of AthensAthensGreece
  2. 2.Institute of Drug Research, School of Pharmacy and David R. Bloom Center for Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

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