Drug interchangeability: Clinical efficacy and safety

The paper deals with the problem of the interchangeability of brand-name and generic drugs. Touching upon official terminology and the normative documents that govern the registration of generics in Russia and foreign countries, the authors state that there is no concerted approach to estimating drug interchangeability, indicate that there are some disadvantages of using a method for proving the bioequivalence of the compared drugs as evidence for their therapeutic equivalence, and point out that Russia’s legal regulation of drug circulation lacks attention to the proper use of generics. The problem of interchangeability is particularly acute when prescribing narrow therapeutic range drugs, including anticonvulsant drugs. The results of the investigations discussed in the article demonstrate the need for a very cautious approach to using generic drugs in the therapy of epilepsy due to the fact that the disease may worsen. The authors come to the conclusion that treatment with less expensive generic drugs is far from always more economical. The change from a brand-name for a generic drug should be carefully approached, basing on the data of properly designed and conducted studies of therapeutic equivalence.

brand-name drug, generic drug, bioequivalence, therapeutic equivalence, narrow therapeutic range, anticonvulsant drugs, epilepsy

1. Гуревич КГ, Мешковский АП. Определение биоэквивалентности: сравнительный подход. Москва: Октябрь; 2001. Т. 2. С. 43 [Gurevich KG, Meshkovskii AP. Opredelenie bioekvivalentnosti: sravnitel'nyi podkhod [Definition of bioequivalence: a comparative approach]. Moscow: Oktyabr'; 2001. Vol. 2. P. 43].

2. Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability. WHO Technical Report Series. 2006;937 Annex 7:347-90.

3. Available from: www.fda.gov

4. Батищева ГА, Мубаракшина ОА, Курбатова ЕИ. Оригинальные и воспроизведенные лекарственные препараты в кардиологи: проблемы взаимозаменяемости препаратов бисопролола. Consilium Medicum. 2016;10:50-4 [Batishcheva GA, Mubarakshina OA, Kurbatova EI. Original and reproduced drugs in cardiologists: problems of the interchangeability of bisoprolol preparations. Consilium Medicum. 2016;10:50-4 (In Russ.)].

5. Федеральный закон «Об обращении лекарственных средств» №61-ФЗ от 12.04.2010 (ред. от 03.07.2016) [Federal Law «On the circulation of medicinal products» No. 61-FZ of 12.04.2010 (as amended on 03.07.2016)].

6. Зырянов СК, Белоусов ЮБ. Проблема качества генериков и оценка их соответствия оригинальным препаратам. Клиническая микробиология и антимикробная химиотерапия. 2010;12(4):314-20 [Zyryanov SK, Belousov YuB. Quality of Generic Drug Products and Equivalence to Original Drug Products. Klinicheskaya Mikrobiologiya i Antimikrobnaya Khimioterapiya. 2010;12(4): 314-20 (In Russ.)].

7. Зырянов СК, Белоусов ЮБ. Оригинальные препараты или дженерики: как выбрать? Журнал неврологии и психиатрии им. С.С Корсакова. Эпилепсия. 2008; 108(S2):43-8 [Zyryanov SK, Belousov YuB. Original drugs or generics: how to choose? Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova = SS Korsakov Journal of Neurology and Psychiatry. 2008;108(S2):43-8 (In Russ.)].

8. Мешковский АП. Зарубежный опыт упрощения выведения новых лекарств на рынок. Фармацевтический вестник. 2014 Июнь; №21 [Meshkovskii AP. Foreign experience of simplifying the introduction of new drugs on the market. Farmatsevticheskii Vestnik. 2014 June; №21 (In Russ.)].

9. Хохлов АЛ, Лилеева ЕГ. Анализ качества проведения исследований биоэквивалентности и фармакокинетики в России. Качественная клиническая практика. 2016;(2): 64-70 [Khokhlov AL, Lileeva EG. Analysis of the quality of bioequivalence and pharmacokinetic studies in Russia. Kachestvennaya Klinicheskaya Praktika. 2016;(2):64-70 (In Russ.)].

10. Meredith PA. Potential concerns about generic substitution: bioequivalence of different amlodipine salt forms. Curr Med Res Opin. 2009;25(9):2179-89. doi: 10.1185/03007990903116867

11. Yu LX, Li B, editors. FDA Bioequivalence Standards. AAPS Advances in the Pharmaceutical Sciences Series. Springer; 2014. 194 p.

12. Yu LX, Jiang W, Zhang X, et al. Novel bioequivalence approach for narrow therapeutic index drugs. Clin Pharmacol Ther. 2015;97(3): 286-91. doi: 10.1002/cpt.28

13. Резолюция заседания рабочей группы Российской противоэпилептической лиги. Эпилепсия и пароксизмальные состояния. 2016;8(4):109-11 [Resolution of the meeting of the working group of the Russian antiepileptic league. Epilepsiya i Paroksizmal'nye Sostoyaniya. 2016;8(4):109-11 (In Russ.)].

14. Hottinger M, Liang BA. Deficiencies of the FDA in evaluating generic formulations: addressing narrow therapeutic index drugs. Amer J Law Med. 2012;38:667-89. doi: 10.1177/009885881203800403

15. Sankar R, Glauser TA. Understanding therapeutic equivalence in epilepsy. CNS Spectr. 2010 Feb;15(2):112-23. doi: 10.1017/S1092852900027358

16. Antiepileptic drugs: new advice on switching between different manufacturers’ products for a particular drug. Available from: www.gov.uk/

17. Atif M, Azeem M, Sarwar MR. Potential problems and recommendations regarding substitution of generic antiepileptic drugs: a systematic review of literature. Springerplus. 2016;5:182. doi: 10.1186/s40064-016-1824-2

18. Sachdeo RC, Belendiuk G. Generic versus branded carbamazepine. Lancet. 1987 Jun 20;1(8547):1432. doi: 10.1016/S0140-6736(87)90619-2

19. Welty TE, Pickering PR, Hale BC, et al. Loss of seizure control associated with generic substitution of carbamazepine. Ann Pharmacother. 1992;26:775-7. doi: 10.1177/106002809202600605

20. Koch G, Allen JP. Untoward effects of generic carbamazepine therapy. Arch Neurol. 1987;44(6):578-9. doi: 10.1001/archneur.1987.00520180004003

21. Hartley R, Aleksandrowicz J, Bowmer CJ, et al. Dissolution and relative bioavailability of two carbamazepine preparations for children with epilepsy. J Pharm Pharmacol. 1991;43(2):117-9. doi: 10.1111/j.2042-7158.1991.tb06644.x

22. Berg MJ, Gross RA, Tomaszewski KJ, et al. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology. 2008;71(7):525-30. doi: 10.1212/01.wnl.0000319958.37502.8e

23. Hartley R, Aleksandrowicz J, Ng PC, et al. Breakthrough seizures with generic carbamazepine: a consequence of poorer bioavailability? Br J Clin Pract. 1990;44(7):270-3.

24. Meyer MC, Straughn AB, Jarvi EJ, et al. The bioinequivalence of carbamazepine tablets with a history of clinical failures. Pharm Res. 1992;9(12):1612-6. doi: 10.1023/A:1015872626887

25. Jain K. Investigation and management of loss of efficacy of an antiepileptic medication using carbamazepine as an example. J R Soc Med. 1993;86(3):133-6.

26. Gilman JT, Alvarez LA, Duchowny M. Carbamazepine toxicity resulting from generic substitution. Neurology. 1993;43(12):2696-7. doi: 10.1212/WNL.43.12.2696

27. Jumao-as A, Bella I, Craig B, et al. Comparison of steady-state blood levels of two carbamazepine formulations. Epilepsia. 1989; 30(1):67-70. doi: 10.1111/j.1528-1157.1989.tb05283.x

28. Reunanen M, Heinonen EH, Nyman L, Anttila M. Comparative bioavailability of carbamazepine from two slow-release preparations. Epilepsy Res. 1992;11(1):61-6. doi: 10.1016/0920-1211(92)90022-L

29. Neuvonen PJ. Bioavailability and central side effects of different carbamazepine tablets. Int J Clin Pharmacol Ther Toxicol. 1985;23(4): 226-32.

30. Olling M, Mensinga TT, Barends DM, et al. Bioavailability of carbamazepine from four different products and the occurrence of side effects. Biopharm Drug Dispos. 1999;20(1):19-

31. doi: 10.1002/(SICI)1099-081X(199901)20:1<19::AID-BDD152>3.0.CO;2-Q

32. Garnett WR, Gilbert TD, O’Connor P. Patterns of care, outcomes, and direct health plan costs of antiepileptic therapy: a pharmacoeconomic analysis of the available carbamazepine formulations. Clin Ther. 2005;27(7):1092-103. doi: 10.1016/j.clinthera.2005.07.008

33. Yamada M, Welty TE. Generic substitution of antiepileptic drugs: a systematic review of prospective and retrospective studies. Ann Pharmacother. 2011;45(11):1406-15. doi: 10.1345/aph.1Q349

34. Soryal I, Richens A. Bioavailability and dissolution of proprietary and generic formulations of phenytoin. J Neurol Neurosurg Psychiatry. 1992;55(8):688-91. doi: 10.1136/jnnp.55.8.688

35. Chen SS, Allen J, Oxley J, Richens A. Comparative bioavailability of phenytoin from generic formulations in the United Kingdom. Epilepsia. 1982;23(2):149-52. doi: 10.1111/j.1528-1157.1982.tb05062.x

36. Margolese HC, Wolf Y, Desmarais JE, Beauclair L. Loss of response after switching from brand name to generic formulations: three cases and a discussion of key clinical considerations when switching. Int Clin Psychopharmacol. 2010;25(3):180-2. doi: 10.1097/YIC. 0b013e328337910b

37. Sherr JD, Kelly DL. Substitution of immediate-release valproic acid for divalproex sodium for adult psychiatric inpatients. Psychiatr Serv. 1998;49(10):1355-7. doi: 10.1176/ps.49.10.1355

38. Levine J, Chengappa KN, Parepally H. Side effect profile of entericcoated divalproex sodium versus valproic acid. J Clin Psychiatry. 2000;61(9):680-1. doi: 10.4088/JCP.v61n0914h

39. Sherwood BE, Shellhorn E, Suppes T. Gastrointestinal side-effects after switch to generic valproic acid. Pharmacopsychiatry. 1998;31(3):114. doi: 10.1055/s-2007-979310

40. Wassef AA, Winkler DE, Roache AL, et al. Lower effectiveness of divalproex versus valproic acid in a prospective, quasi-experimental clinical trial involving 9,260 psychiatric admissions. Am J Psychiatry. 2005;162(2):330-9. doi: 10.1176/appi.ajp.162.2.330

41. Zarate CA Jr, Tohen M, Narendran R, et al. The adverse effect profile and efficacy of divalproex sodium compared with valproic acid: a pharmacoepidemiology study. J Clin Psychiatry. 1999;60(4):232-6. doi: 10.4088/JCP.v60n0405

42. Schwartz TL, Massa JL, Gupta S, et al. Divalproex sodium versus valproic acid in hospital treatment of psychotic disorders. Prim Care Companion J Clin Psychiatry. 2000;2(2):45-8. doi: 10.4088/PCC.v02n0203

43. Armstrong TS, Choi S, Walker J, Gilbert MR. Seizure risk in brain tumor patients with conversion to generic levetiracetam. J Neurooncol. 2010;98(1):137-41. doi: 10.1007/s11060-009-0066-3

44. Fitzgerald CL, Jacobson MP. Generic substitution of levetiracetam resulting in increased incidence of breakthrough seizures. Ann Pharmacother. 2011;45(5):e27. doi: 10.1345/aph.1P765

45. Chaluvadi S, Chiang S, Tran L, et al. Clinical experience with generic levetiracetam in people with epilepsy. Epilepsia. 2011;52(4):810-5. doi: 10.1111/j.1528-1167.2011.03025.x

46. Duh MS, Paradis PE, Latremouille-Viau D, et al. The risks and costs of multiple-generic substitution of topiramate. Neurology. 2009;72(24): 2122-9. doi: 10.1212/WNL.0b013e3181aa5300

47. Pineyro-Lopez A, Pineyro-Garza E, Gomez-Silva M, et al. Bioequivalence of single 100-mg doses of two oral formulations of topiramate: an open-label, randomized-sequence, two-period crossover study in healthy adult male Mexican volunteers. Clin Ther. 2009; 31(2):411-7. doi: 10.1016/j.clinthera.2009.02.001

48. Bankstahl M, Bankstahl JP, Lö scher W. Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy? A pharmacokinetic study with two oral formulations (Luminal® vet, Phenoleptil®) in dogs. BMC Vet Res. 2013;9(1):202. doi: 10.1186/1746-6148-9-202

49. Cook A, Bensalem-Owen M, Owens-Acey T, et al. Pharmacokinetic variations and impact on seizures after brand to generic substitution of oxcarbazepine in adults with epilepsy. In: Epilepsia. Malden: Wiley-Blackwell Publishing, Inc.; 2009. P. 111.

50. Makus KG, McCormick J. Identification of adverse reactions that can occur on substitution of generic for branded lamotrigine in patients with epilepsy. Clin Ther. 2007;29(2):334-41. doi: 10.1016/j.clinthera.2007.02.005

51. Nielsen KA, Dahl M, Tommerup E, Wolf P. Comparative daily profiles with different preparations of lamotrigine: a pilot investigation. Epilepsy Behav. 2008;13(1):127-30. doi: 10.1016/j.yebeh.2008.02.020

52. Srichaiya A, Longchoopol C, Oo-Puthinan S, et al. Bioequivalence of generic lamotrigine 100-mg tablets in healthy Thai male volunteers: a randomized, single-dose, two-period, twosequence crossover study. Clin Ther. 2008;30(10): 1844-51. doi: 10.1016/j.clinthera.2008.10.018

53. Sabroe TP, Sabers A. Progressive anticonvulsant hypersensitivity syndrome associated with change of drug product. Acta Neurol Scand. 2008;117(6):428-31. doi: 10.1111/j.1600-0404.2007.00976.x

54. Andermann F, Duh MS, Gosselin A, Paradis PE. Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia. 2007;48(3):464-9. doi: 10.1111/j.1528-1167.2007.01007.x

55. Wyllie E, Pippenger CE, Rothner AD. Increased seizure frequency with generic primidone. JAMA. 1987;258(9):1216-7. doi: 10.1001/jama.1987.03400090100043

56. Hansen RN, Nguyen HP, Sullivan SD. Bioequivalent antiepileptic drug switching and the risk of seizure-related events. Epilepsy Res. 2013;106:237-43. doi: 10.1016/j.eplepsyres. 2013.04.010

57. Громов СА, Табулина СД. Использование вальпроатов-дженериков (энкорат-хроно) в лечении больных эпилепсией. Журнал неврологии и психиатрии им. С.С. Корсакова. 2005;105(4):22-6 [Gromov SA, Tabulina SD. The use of valproates-generics in the treatment of epileptic patients. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova = SS Korsakov Journal of Neurology and Psychiatry. 2005; 105(4):22-6 (In Russ.)].