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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
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

Transplant Unit, Department of Surgery, University of Cape Town, Cape Town, South Africa

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Date of Web Publication26-Apr-2010


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;21:426-32

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 2022 Aug 10];21:426-32. Available from: https://www.sjkdt.org/text.asp?2010/21/3/426/62705

   Introduction Top

The introduction of cyclosporine (CsA) in the 1980's was responsible for a significant impro­vement in patient and allograft survival. [1] 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. [2],[3],[4],[5],[6],[7],[8],[9] 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 Top

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.

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. [7] Statistical anaylsis: all data is given as mean + SD and student t test was used to com­pare the mean taking P < 0.05 as significant.

   Results Top

There were a total of 319 patients attending the Transplant Clinic at Groote Schuur Hospi­tal. However only 117 patients were on main­tenance cyclosporine. In the remaining 202 pa­tients cyclosporine had either been withdrawn from their immunosuppression protocol and patients maintained on azathioprine and steroids or been replaced by tacrolimus or sirolimus.

Of the 117 patients on cyclosporine, 76 were also receiving ketoconazole to reduce the dose of cyclosporine. There were 60 males and 57 females. 72 of the patients were of mixed racial origin, 24 were white and 21 were black.

The average cyclosporine doses before and after conversion to the generic cyclosporine are shown in [Figure 1]. The mean cyclosporine dose prior to conversion was 53 ± 4 mg and after conversion to the generic cyclosporine was 56 ± 4 mg (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).

   Discussion Top

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. [1] 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. [11],[12]

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. [2],[3],[4],[5],[6],[7],[8],[9] 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. [7],[8],

Several studies have compared the generic formulations to NEO and have shown them to be bioequivalent. [6],[9],[13],[14],[15] 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. [6]

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. [8],[16], 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. [10] 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]

   References Top

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.  Back to cited text no. 1      
2.First MR, Alloway R, Schroeder TJ. Develop­ment of Sang-35: A cyclosporine formulation bioequivalent to Neoral. Clin Transplant 1998; 12:518.  Back to cited text no. 2  [PUBMED]    
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.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
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.  Back to cited text no. 4      
5.Carnahan W, Cooper TY. Neoral-to-Gengraf conversion in renal transplant recipients. Transplant Proc 2003;35:1308.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
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.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
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.  Back to cited text no. 7      
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.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
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.  Back to cited text no. 9      
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.  Back to cited text no. 10  [PUBMED]    
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.  Back to cited text no. 11  [PUBMED]    
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.  Back to cited text no. 12      
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.  Back to cited text no. 13      
14.David-Neto E, Kakehashi E, Alves CF. Bio­equivalence of a new cyclosporine formulation to neural. Ther Dru Monitor 2004;26:53-7.  Back to cited text no. 14      
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.  Back to cited text no. 15      
16.Cattaneo D, Perico N, Remuzzi G. Generic c­yclosporine formulations: More open questions than answers. Transplant Int 2005;18:371-82.  Back to cited text no. 16      

Correspondence Address:
Delawir Kahn
Department of Surgery, Medical School, University of Cape Town Observatory, 7925, Cape Town
South Africa
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Source of Support: None, Conflict of Interest: None

PMID: 20427863

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1]

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