Generic Maintenance Immunosuppression in Solid Organ Transplant Recipients

Christopher R. Ensor, Pharm.D.; Jennifer Trofe-Clark, Pharm.D.; Steven Gabardi, Pharm.D., FCCP; Lisa M. McDevitt-Potter, Pharm.D., FCCP; Michael A. Shullo, Pharm.D.


Pharmacotherapy. 2011;31(11):1111-1129. 

In This Article

Abstract and Introduction


Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immunosuppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.


Solid organ transplantation represents an alternative to imminent death in patients with end-stage heart, lung, or liver diseases, or substantial improvement in quality of life for patients with end-stage kidney or pancreas disease, for those individuals who receive transplants; however, the percentage of the atrisk population who receive transplants is becoming increasingly smaller. Survival after solid organ transplantation has increased substantially in the era of tacrolimus and mycophenolate, which may be due in part to advancements in immunosuppressive agents for the maintenance of allograft patency.[1–5] The previous 20 years have seen the introduction of numerous maintenance immunosuppressive agents, including tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, and everolimus.

Maintenance of the immunosuppressive balance is critical for allograft patency and minimization of adverse effects, and ultimately, is implicated in the long-term survival of solid organ transplant recipients.[6] The degree of immunosuppression required for the prevention of rejection of the allograft in many patients is substantial, particularly in the immediate posttransplantation period. Moreover, acute disturbances in the level of immunosuppression may predispose patients to episodes of toxicity, infection, or allograft rejection.[7]

The question of whether clinically relevant changes in drug exposure would occur with the use of generic immunosuppressive products culminated with the approval of several generic formulations of both unmodified cyclosporine (Sandimmune, Novartis Pharmaceuticals, East Hanover, NJ) and modified cyclosporine microemulsion (Neoral, Novartis Pharmaceuticals; and Gengraf, Abbott Laboratories, Abbott Park, IL).[8,9] The transplant community continues to face this challenge with the approval of generic formulations of tacrolimus in 2009 and mycophenolate mofetil in 2008 (Table 1).[9]


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