Year : 2010 | Volume
: 21 | Issue : 3 | Page : 426--432
Safe conversion to cicloral, a generic cylosporine, in both stable and De Novo renal transplant recipients
Delawir Kahn, Elmi Muller, Michael Pascoe
Transplant Unit, Department of Surgery, University of Cape Town, Cape Town, South Africa
Department of Surgery, Medical School, University of Cape Town Observatory, 7925, Cape Town
Several generic cyclosporine (CsA) formulations have been developed over the last decade and are now widely available. In 2003 our local Health Department replaced Neoral with CicloHexal for the cost benefits, and we were compelled to convert all our renal transplant recipients to the generic CsA formulation. All renal transplant recipients were converted from Neoral to CicloHexal on a 1:1 dose basis in August/September 2003. Study 1 constitutes the retrospective review of all stable renal transplant patients and the CsA dose, CsA level and serum creatinine were noted. Study 2 constitutes the review of the records of de novo transplant patients inititated on CicloHexal compared to matched patients transplanted on Neoral before the conversion and the CsA dose, CsA level and serum creatinine noted (Study 2). There was no difference in the mean CsA dose, CsA level or serum creatinine at one month before conversion (on Neoral) compared to one month after conversion (on CicloHexal) in the 117 stable renal transplant recipients. Similarly, the mean CsA dose, CsA level and serum creatinine in de novo renal transplant recipients on Neoral (n= 26) were similar to those on CicloHexal (n= 23) at about seven and ten days postoperatively. In conclusion both stable and de novo renal transplant patients can be safely converted from Neoral to CicloHexal on a 1:1 dose basis.
|How to cite this article:|
Kahn D, Muller E, Pascoe M. Safe conversion to cicloral, a generic cylosporine, in both stable and De Novo renal transplant recipients.Saudi J Kidney Dis Transpl 2010;21:426-432
|How to cite this URL:|
Kahn D, Muller E, Pascoe M. Safe conversion to cicloral, a generic cylosporine, in both stable and De Novo renal transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Feb 17 ];21:426-432
Available from: http://www.sjkdt.org/text.asp?2010/21/3/426/62705
The introduction of cyclosporine (CsA) in the 1980's was responsible for a significant improvement in patient and allograft survival.  Over the last decade several new potent immunosuppressive agents, such as tacrolimus, sirolimus, mycophenolate mofetil, and the monoclonal antibodies basiliximab and dacluzimab, have been added to the transplant clinician's armamentarium. All of these agents, although extremely effective at reducing the incidence of acute rejection, remain prohibitively expensive.
In 1995 the patent on CsA held by Novartis expired. Since then several generic CsA formulations have been developed and have recently become available. ,,,,,,, As health care costs continue to increase, funding authorities have been pushing for the cheaper generic drugs to be used. In 2003, our local Health Department replaced Neoral CsA (Novartis AG, Basel, Switzerland) with the cheaper generic CsA CicloHexal (Hexal AG, Holzkirchen, Germany). This decision was undertaken purely on the basis of cost reduction and was made without consultation with the responsible clinicians. We were therefore compelled to convert all patients from Neoral (NEO) to CicloHexal (CIC).
In this study we report on our experiences both with converting stable renal transplant recipients from NEO to CIC, and with treating de novo transplant recipients with CIC.
Patients and Methods
The study was approved by the Ethics Committee of the Faculty of Health Sciences of the University of Cape Town. All renal transplant recipients attending the transplant clinic at Groote Schuur Hospital in Cape Town were included in the study. The generic cyclosporine CIC was introduced into the hospital in place of NEO in August/September 2003. All patients were converted from NEO to CIC on a 1:1 dose basis.
Study 1. Stable renal transplant recipients:
All patients with stable renal allograft function long-term after transplantation, and receiving maintenance cyclosporine therapy, were included in the study. The charts of the patients were retrospectively reviewed and the serum creatinine, cyclosporine dose and cyclosporine level at one month before and at one month after conversion from NEO to CIC were recorded.
Study 2. De novo renal transplant recipients:
In this part of the study the new patients undergoing renal transplantation following the introduction of CIC were compared to the patients transplanted just prior to the introduction of CIC. The patients were thus divided into the following groups:
Group 1. Patients undergoing renal transplantation in the period before conversion from NEO to CIC.
Group 2. Patients undergoing renal transplantation in the period after conversion from NEO to CIC.
The charts of the patients were retrospectively reviewed and the cyclosporine dose, cyclosporine level and the serum creatinine level at one week and at ten days post-transplantation were recorded.
Conventional surgical techniques were used for the procurement of the donor organs from the donors and the subsequent implantation of the grafts into the recipients. All patients received standardized peri-operative management, including the following immunosuppression protocol.
All patients received cyclosporine, azathioprine and prednisone. The cyclosporine was commenced immediately preoperatively as an oral bolus dose of 8-10 mg/kg, and continued postoperatively at a dose of 10 mg/kg/per day orally in two divided doses. Cyclosporine levels were monitored three times per week and the dose adjusted to maintain trough levels at 200300 ng/mL in the early postoperative period and 100-200 ng/mL once the patients became stabilized.
The patients received 500 mg methylprednisolone as an intravenous bolus on induction of anaesthesia, and 250 mg and 125 mg intravenously on the first and second postoperative days respectively. The oral prednisone was commenced at a dose of 30 mg per day from the first postoperative day and gradually reduced after the first postoperative month.
Azathioprine was administered intraoperatively at a dose of 100 mg as an intravenous bolus. Postoperatively the patients received oral azathioprine at a dose of 100 mg per day.
Acute rejection episodes were diagnosed clinically, based on an increased serum creatinine level, a decreased urine output, pyrexia, and graft tenderness, and only occasionally confirmed histologically. Treatment consisted of bolus doses of methyprednisolone 500 mg/day for four days. Steroid resistant rejection episodes were treated with anti-thymocyte globulin.
At three months after the transplant, patients with stable renal function were given ketoconazole and the dose of cyclosporine reduced by 80%. Ketoconazole inhibits the metabolism of cyclosporine via the cytochrome P450 system.  Statistical anaylsis: all data is given as mean + SD and student t test was used to compare the mean taking P P> 0.05).
The cyclosporine levels before and after conversion to generic cyclosporine are shown in [Figure 2]. The cyclosporine level prior to conversion was 133 ± 7 ng/mL and after conversion to generic cyclosporine was 132 ± 8 ng/mL (P> 0.05).
The changes in the serum creatinine in the stable renal transplant recipients are shown in [Figure 3]. The average serum creatinine prior to conversion was 142 ± 6 umoL/liter and after conversion to the generic cyclosporine was 135 ± 5 umoL/liter (P> 0.05).
In the second part of the study in de novo renal transplant recipients, there were 26 patients in Group 1 (patients transplanted prior to conversion to the generic cyclosporine), and 23 patients in Group 2 (patients transplanted after the conversion to the generic cyclosporine). The demographics of the two groups of patients were similar with regard to gender, race, age and the number of living related donor and cadaver donor transplants [Table 1].
The mean cyclosporine doses at the end of the first week and on the 10 th post-operative day in the two groups of patients are shown in [Figure 4]. There were no differences in the cyclosporine doses between the patients transplanted with NEO compared to the patients transplanted with CIC, both at the end of the first week (268 mg versus 283 mg, P> 0.05) and at about ten days (277 mg versus 295 mg, P> 0.05) post-operatively.
The average cyclosporine levels in the patients transplanted with NEO compared to the patients transplanted with CIC are shown in [Figure 5]. There was no statistical difference in the cyclosporine levels in the patients transplanted with NEO compared to the patients transplanted with CIC both at the end of the first week (192 versus 213 ng/mL, P> 0.05) and at about ten days post-operatively (220 ng/mL/ versus 247 ng/mL, P> 0.05).
The introduction of CsA in the 1980's is still regarded as one of the most significant events in the history of solid organ transplantation.  The widespread use of CsA resulted in a major reduction in the incidence and severity of acute rejection, and a marked improvement in longterm patient and graft survival.
CsA is not easy to use and has been classified as a critical dose drug. It has a narrow therapeutic index, marked inter and intra-patient variability, and dosing which is based on body weight or body surface area. The narrow therapeutic index implies that there is a small gap between under-dosage, resulting in an increased risk of acute rejection (loss of efficacy), and over-dosage, leading to undesired side-effects such as nephrotoxicity. CsA has also been characterized by a poorly predictable bioavailability and extremely variable pharmacokinetics. The microemulsion formulation of CsA NEO has been a significant improvement and has more consistent bioavailability and pharmacokinetics. Furthermore, there is a strong correlation between CsA exposure and clinical outcome, and therefore meticulous monitoring of CsA pharmcokinetics in individual patients is essential. ,
In other areas in medicine, the use of generic formulations has been readily accepted and been shown to be cost-effective. Use of generic drugs has helped to limit soaring medical costs. In transplantation, following the expiry of the CsA patent in 1995, several generic formulations of CsA have been developed and are now widely available. ,,,,,,, However in view of the unpredictable bioavailability of CsA, and its complex pharmacokinetics, concerns have been expressed about converting patients on Neoral to the generic formulations. ,,
Several studies have compared the generic formulations to NEO and have shown them to be bioequivalent. ,,,, However these studies have been criticized because of the use of healthy subjects and the findings extrapolated to apply to different populations. CsA pharmacokinetics in healthy subjects has been shown to be different from transplant patients. In addition, several of the studies have used single CsA dose administration which is not ideal since CsA absorption does vary with time. Furthermore, the absorption of certain generic formulations has been shown to be affected by apple or orange juice, and by the fat-content of food. 
Despite these and other concerns about converting patients to the generic CsA formulations, our local Health Department replaced NEO with the generic CsA CicloHexal for the apparent cost-benefits. ,, No differences in the CsA levels and renal parameters were noted in stable as well as de novo renal transplant patients. It may be argued that the study period may be too short since CsA does take several weeks to reach a steady state and the conclusions drawn may be too soon.
Mean CsA dose in our stable renal transplant patients was about 50 mg due to the use of ketoconazole thus saving significant costs. We have previously demonstrated an 80% reduction in CsA dose when ketoconazole was used in combination with CsA.  In these patients the mean CsA level was about 130 ng/mL reflecting the low maintenance level we use for patients late after transplantation.
In de novo renal transplant patients mean CsA doses of 275 mg and 295 mg for Neoral and CicloHexal respectively reflect the more conventional dose and without the ketoconazole addition in early post renal transplant period.
Another concern about converting patients to a generic cyclosporine would be the efficacy of the new agent. In this study the cyclosporine dose and the cyclosporine levels remained unchanged after conversion to the generic cyclosporine. Although we did not specifically look at the incidence of acute rejection episodes before and after the conversion to the generic CsA, it was our distinct impression that this was not modified at all.
We also did not identify increased rejection episodes nor increased nephrotoxicity.
It has been advised that patients should be monitored more frequently if conversion to a generic CsA is contemplated. After conversion to CIC we asked the stable renal transplant patients to continue routine follow up and similarly the do novo transplant patients had the level measured according to usual protocol. We did not see any untoward effects from not monitoring patients more frequently. Although several generic CsA formulations have been developed since 1995, there is distinct lack of clinical outcomes data. This is particularly true for the more recent formulations of CsA. Furthermore the quality of the different formulations does vary and findings cannot be extrapolated from one preparation to the next. CIC is based on dispersion of the active agent as opposed to the microemulsion as in Neoral. The use of CIC in renal transplant recipients has been documented only to a limited extent and the present study represents one of the first reports on its clinical use in transplant recipients. In addition the present study includes a relatively large number of patients, and involves both stable patients and De Novo renal transplant recipients.
Thus, in summary, we have shown that CsA doses and levels, and serum creatinine levels, in both stable renal0 transplant patients and De Novo renal transplant recipients were unchanged when patients were converted from Neoral to CicloHexal. Assuming that the two formulations of CsA are bioequivalent and, as we have shown, clinically comparable (similar efficacy, tolerability, dosage, need for monitoring, and accompanying therapy) the use of the most cost effective product would represent the most efficient use of limited resources. [Figure 6]
|1||Hariharan S, Johnson P, Bresnan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Eng J Med 2000;342: 605.|
|2||First MR, Alloway R, Schroeder TJ. Development of Sang-35: A cyclosporine formulation bioequivalent to Neoral. Clin Transplant 1998; 12:518.|
|3||Stephan AG, Barbari A, Masri M, et al. A two year study of the new cyclosporine formulation Consupren in de novo renal transplant patients. Transplant Proc 1998;30:3563.|
|4||Andrysek T, Masri M, Jegorov Z, Veselsky Z, Matha V. Equoral, new cyclosporine drug delivery system, versus neural: A bioequivalence study in healthy volunteers. Transplant Proc 2003;35:207.|
|5||Carnahan W, Cooper TY. Neoral-to-Gengraf conversion in renal transplant recipients. Transplant Proc 2003;35:1308.|
|6||Kees F, Mair G, Dittmar M, Bucher M. Cicloral versus Neoral: A bioequivalence study in healthy volunteers on the influence of a fat rich meal on the bio-availability of Cicloral. Transplant Proc 2004;36:3234-8.|
|7||Johnston A, Belitsky P, Frei U, et al. Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant reciients. Eur J Clin Pharmacol 2004;60:389-95. Ponticelli C. Generic cyclosporine: A word of caution. J Nephrol 2004;17(suppl 8):S20-4.|
|8||Durlik M, Rauch C, Thyroff-Friesinger U, Streu H, Paczek L. Comparison of peak and trough level monitoring of cyclosporine treatment using two modern cyclosporine preparations. Transplant Proc 2003;35:1304-7.|
|9||Gerntholz T, Pascoe MD, Botha JF, Halkett J, Kahn D. The use of a cyclosporin-ketoconazole combination: Making renal transplantation affordable in developing countries. Eur J Clin Pharmacol 2004;60:143-8.|
|10||Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics through concentrations and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993;54: 205-18.|
|11||Schroeder TJ, Hariharan S, First MR. Variations in bioavailability of cyclosporine and relationship to clinical outcome in renal transplant sub-populations. Transplant Proc 1995; 27:837-9.|
|12||Roza A, Tomlanovich S, Merion R, et al. Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation. Transplantation 2002;74:1013-7.|
|13||Masri MA, Haberal M, Rizvi A. The pharmacokinetics of equoral versus neural in stable renal transplant recipients: A multinational multicentre study. Transplant Proc 2004;36:803.|
|14||David-Neto E, Kakehashi E, Alves CF. Bioequivalence of a new cyclosporine formulation to neural. Ther Dru Monitor 2004;26:53-7.|
|15||Alloway RR, Isaacs R, Lake K. Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants. Am J Transplant 2003;3:1211-5.|
|16||Cattaneo D, Perico N, Remuzzi G. Generic cyclosporine formulations: More open questions than answers. Transplant Int 2005;18:371-82.|