Generic Immunosuppression in Solid Organ Transplantation

Abstract

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

Conversion from Brand-Name Neoral to the Generic Ciqorin in Stable Renal Transplant Recipients

“…In particular, the generic product must show that the rate (i.e., maximum concentration, C max ) and extent (i.e., the area under the concentration-time curve [AUC]) to which the active ingredient becomes available at the site of drug action is comparable with the innovator drug under similar conditions. However, transplant societies have raised concerns regarding the validity of extrapolating data derived from healthy subjects to the target patient populations [8][9][10] . Indeed, although most of the generic CsA conversion trials in stable renal transplant recipients found the tested products to have similar pharmacokinetic profiles compared to Neoral [11][12][13][14] , few others have reported significant differences between generic and innovator products [15,16] .…”

Generics: Are all immunosuppression agents created equally?

“…12 Comprehensive data on conversion from generic to brand tacrolimus are not readily available. [18][19][20][21][22] A recent tacrolimus conversion study did identify a significantly lower concentration to dose ratio. 18 This phenomenon was seen in nearly 40% of the kidney transplantation recipients receiving generic tacrolimus.…”

“…Unfortunately, this has not been the real life experience in a market with eight generic forms of tacrolimus. [17][18][19][20][21][22] Patients frequently present having been converted to generics without any notification or explanation by their local pharmacist. In our experience and that of other programs identified multiple long-term stable patients that have presented in acute rejection having been converted by their pharmacist without careful trough monitoring resulting in subtherapeutic trough levels.…”

New Onset Hypertension Linked to Generic Cyclosporine Substitution in Post-Renal Transplant Patient

“…Pharmacokinetic disparities were reported among several cyclosporine preparations in African Americans and in children [8] . The method of determining bioequivalence may not be adequate for immunosuppressive drugs, since it does not include actual transplant patients [10] .…”