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      Conversion to generic cyclosporine A in stable chronic patients after heart transplantation

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          Abstract

          Background

          Cyclosporine A (CSA) is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra-individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated.

          Methods

          Twenty adult stable chronic (>24 months post heart transplant) recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral® to the generic CSA (Equoral®) according to the patients’ preference during the clinical routine. Dose-normalized trough levels (DNL) and trough levels (C0) at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared.

          Results

          The mean DNL (adapted to the daily CSA dose in mg) was 0.71±0.26 (ng/mL)/mg on Neoral therapy; on Equoral it was 0.68±0.23 (ng/mL)/mg, ( P=0.38). In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67±39.81 mg versus Equoral 134.58±41.61 mg; P=0.13). No rejection episodes requiring therapy occurred prior to or postconversion ( P=0.99). Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant). No adverse events after the conversion were observed.

          Conclusion

          This study in chronic and stable HTx patients demonstrated no statistically significant differences in the CSA DNL after a conversion to generic CSA (Equoral). The generic CSA was generally well-tolerated. We concluded that a conversion from Neoral to Equoral is safe and clinically feasible in this distinct patient population. However, multiple switches between different generic immunosuppressants must especially be avoided in the interest of patient safety, and close follow-up examinations must be warranted.

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          Most cited references 11

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          Generic immunosuppression in solid organ transplantation: a Canadian perspective.

          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.
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            History of the discovery of cyclosporin and of its early pharmacological development.

             F Borel (2002)
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              The clinical benefits of cyclosporine C2-level monitoring: a systematic review.

              Monitoring of cyclosporine microemulsion (Neoral) using 2-hour postdose (C2) levels is alleged to improve clinical outcomes, but the efficacy of this strategy is uncertain. A systematic literature search was performed for trials directly comparing patients monitored with C2 levels with those monitored by trough (C0) levels. Primary outcomes assessed were renal function and acute rejection. A total of 29 studies met the inclusion criteria. Only 10 of these were randomized controlled trials. Overall quality was poor and this precluded meta-analysis. The most consistent finding in de novo renal, hepatic, and cardiac transplant recipients is a higher mean cyclosporine dose in the early postoperative period in C2 monitored patients. There is no clear evidence that this leads to impaired renal function. In the majority of studies, the monitoring strategy had no significant effect on the rate of acute rejection. In stable transplant recipients, the majority of studies show a reduction in mean cyclosporine dose with adoption of C2 monitoring. No obvious clinical benefit was derived from this reduction in dose. In de novo transplant patients, there is little evidence from prospective studies to support the theoretical benefits of C2 monitoring. Potential dose reductions in stable patients may reduce costs, but no short-term clinical benefit is seen. Quality of studies in this area is poor, and the practical limitations of C2 monitoring mean that further evidence is required before a strategy for the administration of cyclosporine based on C2 levels can be recommended.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2013
                28 November 2013
                : 7
                : 1421-1426
                Affiliations
                [1 ]Department of Cardiology, University of Heidelberg, Heidelberg, Germany
                [2 ]Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
                Author notes
                Correspondence: Andreas O Doesch, Medizinische Klinik III, Kardiologie, Angiologie and Pneumologie, Ebene 00, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany, Tel +49 6221 56 39 936, Fax +49 6221 56 41 05, Email andreas.doesch@ 123456med.uni-heidelberg.de
                Article
                dddt-7-1421
                10.2147/DDDT.S54245
                3849002
                © 2013 Kraeuter et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

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