Generic immunosuppressants

  • Mara Medeiros
  • Julia Lumini
  • Noah Stern
  • Gilberto Castañeda-Hernández
  • Guido Filler
Educational Review

Abstract

Immunosuppressive drugs for solid organ transplantation are critical dose drugs with a narrow therapeutic index. Many of the most commonly used innovator drugs are off patent and have been replicated by generic counterparts, often at substantial cost-savings to the patient. However, serious adverse events caused by the transition from innovator to generic medications, specifically in pediatric solid organ transplant recipients, have questioned these autosubstitutions. The purpose of this review is to summarize the criteria set forth by the regulatory bodies, and to examine how major immunosuppressive drugs conform to these recommendations. Regulatory bodies have established inconsistent criteria to demonstrate bioequivalence between innovator and generic medications, causing approved generic variations to have varying levels of equivalence with the innovator drugs. In order to minimize the risk for under-immunosuppression, the following recommendations have been concluded. Brand prescribing of cyclosporine and tacrolimus are recommended due to evidence of adverse events after conversion to generic formulations and differences in dissolution parameters. Mycophenolate mofetil (MMF) shows better bioequivalence between innovator and generic formulations, however caution should be advised when switching between formulations. The institution of ‘innovator only’ policies may be appropriate at this time in order to minimize the risk of under-immunosuppressing patients until the evidence of more stringent bioequivalence has been established.

Keywords

Calcineurin inhibitors mTOR inhibitors Antimetabolites MMF Tacrolimus Sirolimus 

References

  1. 1.
    Boumil MM, Curfman GD (2013) On access and accountability—two Supreme Court rulings on generic drugs. N Engl J Med 369:696–697CrossRefPubMedGoogle Scholar
  2. 2.
    Hemphill CS, Sampat BN (2012) Evergreening, patent challenges, and effective market life in pharmaceuticals. J Health Econ 31:327–339CrossRefPubMedGoogle Scholar
  3. 3.
    Debnath B, Al-Mawsawi LQ, Neamati N (2010) Are we living in the end of the blockbuster drug era? Drug News Perspect 23:670–684CrossRefPubMedGoogle Scholar
  4. 4.
    http://www.prnewswire.com/news-releases/mylan-applauds-study-highlighting-1-trillion-in-savings-for-us-health-care-system-due-to-generic-drugs-over-past-decade-164758956.html - Press Release from Aug 2, 2012. Accessed 14-Jun-2017Google Scholar
  5. 5.
    Jacobo-Cabral CO, Garcia-Roca P, Reyes H, Lozada-Rojas L, Cruz-Antonio L, Medeiros M, Castaneda-Hernandez G (2014) Limustin(R), a non-innovator tacrolimus formulation, yields reduced drug exposure in pediatric renal transplant recipients. Pediatr Transplant 18:706–713CrossRefPubMedGoogle Scholar
  6. 6.
    Duong SQ, Lal AK, Joshi R, Feingold B, Venkataramanan R (2015) Transition from brand to generic tacrolimus is associated with a decrease in trough blood concentration in pediatric heart transplant recipients. Pediatr Transplant 19:911–917CrossRefPubMedGoogle Scholar
  7. 7.
    Madian AG, Panigrahi A, Perera MA, Pinto N (2014) Case report: inability to achieve a therapeutic dose of tacrolimus in a pediatric allogeneic stem cell transplant patient after generic substitution. BMC Pharmacol Toxicol 15:69CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Filler G, Kobrzynski M (2014) The problem with generic immunosuppressants. Pediatr Transplant 18:551–553CrossRefPubMedGoogle Scholar
  9. 9.
    Tsipotis E, Gupta NR, Raman G, Zintzaras E, Jaber BL (2016) Bioavailability, efficacy and safety of generic immunosuppressive drugs for kidney transplantation: a systematic review and meta-analysis. Am J Nephrol 44:206–218CrossRefPubMedGoogle Scholar
  10. 10.
    Ravichandran B, Weir MR (2016) The tyranny of generic Immunosuppressants. Am J Nephrol 44:204–205CrossRefPubMedGoogle Scholar
  11. 11.
    Food and Drug Administration (2014) Abbreviated New Drug Application (ANDA): GenericsGoogle Scholar
  12. 12.
    Langguth P, Fricker G, Wunderli-Allenspach H (2004) Biopharmazie. Wiley-VCH Verlag GmbH & Co KGaA:79–162, 165–286Google Scholar
  13. 13.
    Sabatini S, Ferguson RM, Helderman JH, Hull AR, Kirkpatrick BS, Barr WH (1999) Drug substitution in transplantation: a National Kidney Foundation white paper. Am J Kidney Dis 33:389–397CrossRefPubMedGoogle Scholar
  14. 14.
    Karamehic J, Ridic O, Ridic G, Jukic T, Coric J, Subasic D, Panjeta M, Saban A, Zunic L, Masic I (2013) Financial aspects and the future of the pharmaceutical industry in the United States of America. Mater Sociomed 25:286–290CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Molnar AO, Fergusson D, Tsampalieros AK, Bennett A, Fergusson N, Ramsay T, Knoll GA (2015) Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. BMJ 350:h3163CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Borel JF, Feurer C, Magnee C, Stahelin H (1977) Effects of the new anti-lymphocytic peptide cyclosporin a in animals. Immunology 32:1017–1025PubMedPubMedCentralGoogle Scholar
  17. 17.
    Margreiter R (1991) Impact of cyclosporine on organ transplantation. Transplant Proc 23:2180–2182PubMedGoogle Scholar
  18. 18.
    Filler G, Ehrich J (1996) Which cyclosporin formulation? Lancet 348:1176–1177CrossRefPubMedGoogle Scholar
  19. 19.
    Al Wakeel JS, Shaheen FA, Mathew MC, Abouzeinab HM, Al Alfi A, Tarif NM, Al Mousawi MS, Mahmoud TS, Alorrayed AS, Fagir EA, Dham RS, Shaker DS (2008) Therapeutic equivalence and mg:mg switch ability of a generic cyclosporine microemulsion formulation (Sigmasporin Microral) in stable renal transplant patients maintained on Sandimmun Neoral. Transplant Proc 40:2252–2257CrossRefPubMedGoogle Scholar
  20. 20.
    Fradette C, Lavigne J, Waters D, Ducharme MP (2005) The utility of the population approach applied to bioequivalence in patients: comparison of 2 formulations of cyclosporine. Ther Drug Monit 27:592–600CrossRefPubMedGoogle Scholar
  21. 21.
    Hibberd AD, Trevillian PR, Roger SD, Wlodarczyk JH, Stein AM, Bohringer EG, Milson-Hawke SM (2006) Assessment of the bioequivalence of a generic cyclosporine a by a randomized controlled trial in stable renal recipients. Transplantation 81:711–717CrossRefPubMedGoogle Scholar
  22. 22.
    Masri MA, Haberal M, Rizvi A, Stephan A, Bilgin N, Naqvi A, Barbari A, Kamel G, Zafar N, Emiroglu R, Colak T, Manzoor K, Matha V, Kamarad V, Rost M, Rizk S, Hazime A, Perlik F (2005) Switchability of Neoral and Equoral according to Food and Drug Administration rules and regulations. Transplant Proc 37:2988–2993CrossRefPubMedGoogle Scholar
  23. 23.
    Perlik F, Masri MA, Rost M, Kamarad V (2005) Pharmacokinetic conversion study of a new cyclosporine formulation in stable adult renal transplant recipients. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 149:309–313CrossRefPubMedGoogle Scholar
  24. 24.
    Roza A, Tomlanovich S, Merion R, Pollak R, Wright F, Rajagopalan P, Pruett T, Scandling J, Ryan J, Awni W, Schweitzer S, Greco R, Lam W, Nabulsi A, Hoffman R (2002) Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation. Transplantation 74:1013–1017CrossRefPubMedGoogle Scholar
  25. 25.
    First MR, Alloway R, Schroeder TJ (1998) Development of sang-35: a cyclosporine formulation bioequivalent to Neoral. Clin Transpl 12:518–524Google Scholar
  26. 26.
    Fisher RA, Pan SH, Rossi SJ, Schroeder TJ, Irish WD, Canafax DM, Lopez RR (1999) Pharmacokinetic comparison of two cyclosporine a formulations, SangCya (sang-35) and Neoral, in stable adult liver transplant recipients. Transplant Proc 31:394–395CrossRefPubMedGoogle Scholar
  27. 27.
    Gaston R, Alloway RR, Gaber AO, Rossi SJ, Schroeder TJ, Irish WD, Canafax DM, First MR (1999) Pharmacokinetic and safety evaluation of SangCya vs Neoral or Sandimmune in stable renal transplant recipients. Transplant Proc 31:326–327CrossRefPubMedGoogle Scholar
  28. 28.
    Khatami SM, Taheri S, Azmandian J, Sagheb MM, Nazemian F, Razeghi E, Shahidi S, Sadri F, Shamshiri AR, Sayyah M (2015) One-year multicenter double-blind randomized clinical trial on the efficacy and safety of generic cyclosporine (Iminoral) in de novo kidney transplant recipients. Exp Clin Transplant 13:233–238PubMedGoogle Scholar
  29. 29.
    Riva N, Guido PC, Ibanez J, Licciardone N, Rousseau M, Mato G, Monteverde M, Schaiquevich P (2014) Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin. Int J Clin Pharm 36:779–786CrossRefPubMedGoogle Scholar
  30. 30.
    Wallemacq PE, Verbeeck RK (2001) Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 40:283–295CrossRefPubMedGoogle Scholar
  31. 31.
    Trompeter R, Filler G, Webb NJ, Watson AR, Milford DV, Tyden G, Grenda R, Janda J, Hughes D, Ehrich JH, Klare B, Zacchello G, Bjorn Brekke I, McGraw M, Perner F, Ghio L, Balzar E, Friman S, Gusmano R, Stolpe J (2002) Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 17:141–149CrossRefPubMedGoogle Scholar
  32. 32.
    Filler G, Trompeter R, Webb NJ, Watson AR, Milford DV, Tyden G, Grenda R, Janda J, Hughes D, Offner G, Klare B, Zacchello G, Brekke IB, McGraw M, Perner F, Ghio L, Balzar E, Friman S, Gusmano R, Stolpe J (2002) One-year glomerular filtration rate predicts graft survival in pediatric renal recipients: a randomized trial of tacrolimus vs cyclosporine microemulsion. Transplant Proc 34:1935–1938CrossRefPubMedGoogle Scholar
  33. 33.
    Filler G, Webb NJ, Milford DV, Watson AR, Gellermann J, Tyden G, Grenda R, Vondrak K, Hughes D, Offner G, Griebel M, Brekke IB, McGraw M, Balzar E, Friman S, Trompeter R (2005) Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant 9:498–503CrossRefPubMedGoogle Scholar
  34. 34.
    Amidon GL, Lennernas H, Shah VP, Crison JR (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413–420CrossRefPubMedGoogle Scholar
  35. 35.
    Lobenberg R, Amidon GL (2000) Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm 50:3–12CrossRefPubMedGoogle Scholar
  36. 36.
    Petan JA, Undre N, First MR, Saito K, Ohara T, Iwabe O, Mimura H, Suzuki M, Kitamura S (2008) Physiochemical properties of generic formulations of tacrolimus in Mexico. Transplant Proc 40:1439–1442CrossRefPubMedGoogle Scholar
  37. 37.
    Abdulnour HA, Araya CE, Dharnidharka VR (2010) Comparison of generic tacrolimus and Prograf drug levels in a pediatric kidney transplant program: brief communication. Pediatr Transplant 14:1007–1011CrossRefPubMedGoogle Scholar
  38. 38.
    Zhao W, Fakhoury M, Baudouin V, Storme T, Maisin A, Deschenes G, Jacqz-Aigrain E (2013) Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients. Eur J Clin Pharmacol 69:189–195Google Scholar
  39. 39.
    Filler G, Lepage N (2004) To what extent does the understanding of pharmacokinetics of mycophenolate mofetil influence its prescription. Pediatr Nephrol 19:962–965PubMedGoogle Scholar
  40. 40.
    Smith JM, Martz K, Blydt-Hansen TD (2013) Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: a report of the north American pediatric renal trials and collaborative studies. Pediatr Transplant 17:149–157CrossRefPubMedGoogle Scholar
  41. 41.
    NAPRTCS (2010) (https://web.emmes.com/study/ped/annlrept/2010_Report.pdf. accessed February 16th, 2014)
  42. 42.
    Downing HJ, Pirmohamed M, Beresford MW, Smyth RL (2013) Paediatric use of mycophenolate mofetil. Br J Clin Pharmacol 75:45–59Google Scholar
  43. 43.
    Dipchand AI, Benson L, McCrindle BW, Coles J, West L (2001) Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience. Pediatr Transplant 5:112–118CrossRefPubMedGoogle Scholar
  44. 44.
    Filler G, Alvarez-Elias AC, McIntyre C, Medeiros M (2017) The compelling case for therapeutic drug monitoring of mycophenolate mofetil therapy. Pediatr Nephrol 32:21–29CrossRefPubMedGoogle Scholar
  45. 45.
    Le Meur Y, Buchler M, Thierry A, Caillard S, Villemain F, Lavaud S, Etienne I, Westeel PF, Hurault de Ligny B, Rostaing L, Thervet E, Szelag JC, Rerolle JP, Rousseau A, Touchard G, Marquet P (2007) Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant 7:2496–2503CrossRefPubMedGoogle Scholar
  46. 46.
    van Gelder T, Silva HT, de Fijter JW, Budde K, Kuypers D, Tyden G, Lohmus A, Sommerer C, Hartmann A, Le Meur Y, Oellerich M, Holt DW, Tonshoff B, Keown P, Campbell S, Mamelok RD (2008) Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation 86:1043–1051CrossRefPubMedGoogle Scholar
  47. 47.
    Kuypers DR, Le Meur Y, Cantarovich M, Tredger MJ, Tett SE, Cattaneo D, Tonshoff B, Holt DW, Chapman J, Gelder T (2010) Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol 5:341–358CrossRefPubMedGoogle Scholar
  48. 48.
    Tonshoff B, David-Neto E, Ettenger R, Filler G, van Gelder T, Goebel J, Kuypers DR, Tsai E, Vinks AA, Weber LT, Zimmerhackl LB (2011) Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev (Orlando) 25:78–89CrossRefGoogle Scholar
  49. 49.
    Filler G, Todorova EK, Bax K, Alvarez-Elias AC, Huang SH, Kobrzynski MC (2016) Minimum mycophenolic acid levels are associated with donor-specific antibody formation. Pediatr Transplant 20:34–38CrossRefPubMedGoogle Scholar
  50. 50.
    Masri MA, Andrysek T, Rizk S, Matha V (2004) The role of generics in transplantation: TM-MMF versus Cellcept in healthy volunteers. Transplant Proc 36:84–85CrossRefPubMedGoogle Scholar
  51. 51.
    Patel S, Chauhan V, Mandal J, Shah S, Patel K, Saptarshi D, Maheshwari K, Jha PK, Kale P, Patel K, Mathew P (2011) Single-dose, two-way crossover, bioequivalence study of mycophenolate mofetil 500 mg tablet under fasting conditions in healthy male subjects. Clin Ther 33:378–390CrossRefPubMedGoogle Scholar
  52. 52.
    Sunder-Plassmann G, Reinke P, Rath T, Wiecek A, Nowicki M, Moore R, Lutz J, Gaggl M, Ferkl M (2012) Comparative pharmacokinetic study of two mycophenolate mofetil formulations in stable kidney transplant recipients. Transpl Int 25:680–686CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Soderlund C, Radegran G (2015) Safety and efficacy of the switch to generic mycophenolate mofetil and tacrolimus in heart transplant patients. Clin Transpl 29:619–628CrossRefGoogle Scholar
  54. 54.
    Gonzalez-Ramirez R, Gonzalez-Banuelos J, Villa Mde L, Jimenez B, Garcia-Roca P, Cruz-Antonio L, Castaneda-Hernandez G, Medeiros M (2014) Bioavailability of a generic of the immunosuppressive agent mycophenolate mofetil in pediatric patients. Pediatr Transplant 18:568–574CrossRefPubMedGoogle Scholar
  55. 55.
    van Gelder T, Hesselink DA (2015) Mycophenolate revisited. Transplant Int 28:508–515CrossRefGoogle Scholar
  56. 56.
    Harrison JJ, Schiff JR, Coursol CJ, Daley CJ, Dipchand AI, Heywood NM, Keough-Ryan TM, Keown PA, Levy GA, Lien DC, Wichart JR, Cantarovich M (2012) Generic immunosuppression in solid organ transplantation: a Canadian perspective. Transplantation 93:657–665CrossRefPubMedGoogle Scholar
  57. 57.
    Allard J, Fortin MC (2014) Is it ethical to prescribe generic immunosuppressive drugs to renal transplant patients? Can J Kidney Health Dis 1:23CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1.Unidad de Investigacion en Nefrologia, Hospital Infantil de Mexico Federico GomezMexico CityMexico
  2. 2.Departamento de Farmacología, Facultad de MedicinaUniversidad Nacional Autónoma de MéxicoMexico CityMexico
  3. 3.Department of Biomedical Life SciencesUniversity of WaterlooWaterlooCanada
  4. 4.Department of Paediatrics, Schulich School of Medicine & DentistryUniversity of Western OntarioLondonCanada
  5. 5.Departamento de FarmacologíaEntro de Investigacion y Estudios Avanzados IPNMexico CityMexico
  6. 6.Department of Medicine, Schulich School of Medicine & DentistryUniversity of Western OntarioLondonCanada
  7. 7.Department of Pathology and Laboratory Medicine, Schulich School of Medicine & DentistryUniversity of Western OntarioLondonCanada
  8. 8.Paediatric NephrologyUniversity of Western Ontario, Children’s Hospital, London Health Science CentreLondonCanada

Personalised recommendations