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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2005  |  Volume : 16  |  Issue : 2  |  Page : 140-145
Mycophenolate Sodium versus Mycophenolate Mofetil: A Review of Their Comparative Features


Lecturer in Clinical Pharmacy, University of Auckland, Auckland, NewZealand

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How to cite this article:
Zolezzi M. Mycophenolate Sodium versus Mycophenolate Mofetil: A Review of Their Comparative Features. Saudi J Kidney Dis Transpl 2005;16:140-5

How to cite this URL:
Zolezzi M. Mycophenolate Sodium versus Mycophenolate Mofetil: A Review of Their Comparative Features. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2019 Sep 20];16:140-5. Available from: http://www.sjkdt.org/text.asp?2005/16/2/140/32932

   Introduction Top


Enteric-coated mycophenolate sodium (ECMS) (Myofortic®, Novartis Inc.) was approved by the Saudi Arabian Ministry of Health in April 2003, shortly after this new product was received its first regulatory approval in Switzerland in October 2002. Since then, ECMS has gained approval in more than 36 countries around the world. ECMS also com­plied with the European Mutual Recognition Procedure (MRP) and was approved for the prevention of acute rejection in kidney allo­grafts in adult patients in February 2004. Also, in March 2004, the U.S. Food and Drug Administration (FDA) approved it to be used in combination with cyclosporine and corticosteroids to prevent organ rejection in kidney transplant patients. [1] The FDA based its approval on the results of two randomized, multicenter, double-blind clinical trials of more than 700 newly transplanted (de novo) and maintenance renal transplant patients, compared to mycophenolate mofetil (MMF). [2],[3] These studies and some additional recent literature on ECMS and MMF will be reviewed in this article.


   An Overview of ECMS Top


ECMS is a new enteric-coated formulation that delivers the active moiety mycophenolic acid (MPA), which was first isolated from the mold Penicillin glaucum in 1898. [4] MPA inhibits inosine monophosphate dehydrogenase (IMPDH), a vital enzyme in the de novo synthesis of guanosine nucleotide, preventing its incorporation to DNA; thus inhibiting the growth and division of lymphocytes. [5] MPA is the same active moiety delivered by the pro-drug MMF (Cellcept®, Roche Pharma­ceuticals), which is combined to the mofetil moiety to improve the agent's oral bio­availability. [6]

Gastrointestinal (GI) side effects have signi­ficantly limited the effective utilization of MPA-containing agents, such as MMF. ECMS was designed to reduce the adverse GI events of MPA (in particular nausea, vomiting, dys­pepsia and abdominal pain), while allowing more sustained absorption of the MPA delivered to the small intestine. [7] This was evidenced by ECMS's longer time to achieve peak plasma concentration (2 hours) compared to MMF (0.8 hours) [7] , thereby reducing the potential for upper GI toxicity. It has also been suggested that higher and more sustained exposure to MPA may be achieved with ECMS, [7],[8] which may in turn improve out­comes in renal transplanted patients. [9]


   Clinical Efficacy and Safety Top


Two important pivotal phase III clinical trials [2],[3],[10] (known as ERL B301 and ERL B302) which investigated the efficacy and safety of ECMS in renal transplantation are summarized in [Table - 1].

Results of Trial 1 - ERL B301: Efficacy and Safety

This trial measured the efficacy and toler­ability of ECMS versus MMF. The two groups were well matched for patient characteristics. Comparable efficacy was demonstrated in the first six months post transplantation; acute rejection rates were 20.7% for the ECMS group versus 22.4% for the MMF group (p was not significant). Rates of death, graft loss, and loss to follow-up were also similar. Notably, there was a comparable frequency of adverse events (including those involving the gastro­intestinal tract) between the two groups.

Results of trial 2 - ERL B302: Tolerability and Safety

The goal of this trial was to evaluate the safety and tolerability of ECMS in order to establish whether stable renal transplant reci­pients on MMF could be safely converted to ECMS. The primary end point of evaluating the incidence and severity of gastrointestinal events and neutropenia in the first three months was reached with no significance between the two groups. Furthermore, the frequency of acute rejection, graft loss, death, and loss to follow-up was 3.1% for the ECMS and 3.7% for the MMF group (p was not significant).

In both studies, ECMS treatment sustained higher systemic MPA exposure over time, although overall the efficacy was not superior. The FDA's decision on ECMS was based on the results of these trials, which involved more than 700 de novo and maintenance renal transplant patients.

Both hematological and gastrointestinal adverse events are associated with the use of MPA­containing agents such as MMF and ECMS. These adverse events include anemia, increased risk of opportunistic infections, nausea, vomit­ing, diarrhea, gastritis and ulcers. [7] In previous studies with MMF (typical dose 2g per day), various GI side effects have been observed in up to 48% of patients: nausea/vomiting in up to 34%, abdominal pain in 25%, and stomach discomfort in 10%. In the pivotal clinical trials discussed above, ECMS and MMF showed similar adverse event profiles. The most common adverse reactions associated with ECMS in clinical trials include constipation, nausea, diarrhea and nasopharyngitis in main­tenance patients. Adverse events reported in more than 20% of patients receiving combi­nation therapy with cyclosporine and cortico­steroids in the 12-month de novo renal study and maintenance renal studies were similar between patient groups receiving ECMS and MMF. [3]


   Therapeutic Considerations Top


The results from the studies presented in this review showed no statistically significant differences in the safety or efficacy between ECMS and MMF. Studies have reported that up to 7% of patients taking MMF required at least one dose change. [11],[12] Patients who underwent an initial reduction in MMF dose were eight times more likely to suffer acute organ rejection than those who had not had a dose adjustment. [12] For these patients, ECMS may be a suitable alternative.


   Prescribing Information for ECMS Top


1. Dose and Administration

ECMS is currently available as delayed­release tablets containing either 180- or 360-mg of MPA. Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, povidone (K-30), and starch. [13] The recommended dose in adult renal transplantation is 720 mg twice daily (BID), preferably on an empty stomach, one hour before or two hours after food intake. [13] No dosage adjustment is required in renal insufficiency; however, in patients with creatinine clearance of less than 10 ml/min, patients should be monitored for signs of MPA toxicity. [4] Although no differences in responses between the elderly and younger patients have been identified in clinical trials, dose selection in the elderly should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. [13]

In pediatric patients the dose must be adjusted according to body surface area (BSA). The current recommended dose is 400 mg/m 2 BID, up to a maximum of 720 mg BID. [13] These dosing recommendations are based on the results of one study, which reported that the pharmacokinetic profile of ECMS in pediatric patients was similar to that seen in the adult population. [4],[14] However, further efficacy and safety data in this age group is necessary.

Patients should be advised that the tablets are not to be crushed, chewed, or cut prior to ingestion. The tablets should be swallowed whole in order to preserve the integrity of the enteric coating. [13] Some studies have indicated that high fat meals may affect the rate of absorption of this medication. To avoid the variability in MPA absorption between doses, ECMS should be taken on an empty stomach. [13]

2. Precautions and Monitoring Parameters

In general terms, patients receiving immuno­suppressive regimens involving combinations of drugs, including ECMS, as part of an immunosuppressive regimen are at increased susceptibility to infection, the possible develop­ment of lymphomas and other neoplasms, particularly of the skin. However, this risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. [13]

In view of the above risks, patients receiving ECMS should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. It is recom­mended to perform a complete blood count weekly for the first month, twice a month for the second and third month of treatment, and monthly for the following nine months. If neutropenia develops, the dose of ECMS must be adjusted accordingly. [13]

The US FDA has assigned ECMS a preg­nancy category of C; that is, it should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus.

Although there are no adequate, well-controlled studies in pregnant women, teratology studies performed in animals who received ECMS, malformations in the offspring were observed. [13]

3. Drug Interactions

Not many studies are available reporting drug interactions with ECMS, and it is important to keep in mind that some interactions reported with MMF may also occur with ECMS. [Table - 2] lists a few of the reported interactions with ECMS. [4],[13] Also, drugs that alter the GI flora may interact with ECMS by disrupting the entero-hepatic recirculation. Interference of mycophenolic acid glucoronide, the predomi­nant metabolite of MPA, may also lead to less MPA available for absorption. [13]


   Comparative Features with MMF Top


It is important to understand that MPA is the active moiety delivering the immuno­suppressive characteristics of both, ECMS and MMF. The main difference between the two is that MMF needs to be metabolized first to the active MPA whereas ECMS is an enteric-coated formulation of MPA. Unlike MMF, which is absorbed in the stomach, ECMS is mainly absorbed in the small intestine.

An important issue that has been discussed in the literature as being of particular import­ance when comparing these two medications is the suggestive evidence that the therapeutic efficacy of MPA is enhanced when its systemic exposure, expressed as AUC (0-24h), is greater than 30 µg/ml. [9] At standard doses, ECMS was able to consistently achieve this target. [8] However, in the two pivotal clinical trials described previously, this did not result in a statistically significant difference in reduction in allograft rejection, graft loss, or patient death when compared with MMF. [2],[3] Other differences between the two salts are summarized in [Table - 3]. [4],[13]


   Switching Patients from MMF to ECMS Top


A pivotal, 12-month, phase III, randomized, multicenter, double-blind, double-dummy, parallel group study was designed to establish whether maintenance renal transplant patients receiving MMF could be converted to ECMS therapy without compromising the safety and efficacy profile. [15] The primary safety endpoints were incidence and severity of GI adverse events at 3 months and incidence of neutropenia, defined as <1500 cells/mm 3 , within the first 3 months. Secondary endpoints included evaluation of the overall safety and efficacy profiles. Patients received either ECMS, 720 mg BID or MMF, 1000 mg BID for 12 months.

The results showed a trend favoring ECMS for GI adverse event severity scores suggesting a potential benefit afforded by the enteric­coated formulation of MPA. In terms of efficacy, there was a trend toward ECMS patients expe­riencing fewer efficacy failures (composite variable of biopsy-proven acute rejection, graft loss, death, or loss to follow-up) during the 12­month study period. A similar report by other researchers has also been recently published. [16]

Although this trial suggests that maintenance renal transplant patients receiving MMF can be converted to ECMS with no efficacy or tolerability compromise, these results need to be confirmed in larger trials. When consi­dering this switch, it is important to keep in mind that ECMS and MMF tablets and capsules should not be used interchangeably without physician supervision because the rate of absorption following administration of these two products is not equivalent. [13]


   Pharmacoeconomic Considerations Top


All currently available pharmacoeconomic studies compare MMF with azathioprine. Analysis of the economic implications of using ECMS over MMF has not been addressed in any available reports today, thus it needs to be investigated. However, on the basis of direct drug acquisition costs, ECMS has been marketed in some countries at a slightly lower cost than MMF, at equivalent doses for renal transplantation in adults.


   Conclusions Top


Considering the limited number of studies comparing these two agents, it is difficult to establish significant concluding remarks of the advantages of using ECMS over MMF. What is obvious, however, is that ECMS does represent an alternative to the significant number of patients suffering from the common gastrointestinal intolerance reported with MMF. Whether ECMS's consistent capacity to achieve the target AUC (0-24) of >30 µg/ml is of clinical relevance needs further investigation.

 
   References Top

1.Myfortic® FDA Approval History. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Prescribing Information. URL (accessed August 1, 2004): http://www.fda.gov/cder/foi/appletter/2004/50791ltr.pdf  Back to cited text no. 1    
2.Salvadori M, Holzer H, De Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004;4(2):231-6.  Back to cited text no. 2    
3.Budde K, Curtis J, Knoll G, et al. Enteric­coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant 2004;4(2):237-43.  Back to cited text no. 3    
4.Gabardi S, Tran JL, Clarkson MR. Enteric­coated mycohphenolate sodium. Ann Pharmacother 2003; 37(11):1685-93.  Back to cited text no. 4    
5.Watts RW. Some regulatory and integrative aspects of purine nucleotide biosynthesis and its control: an overview. Adv Enzyme Regul 1983;21:33-51.  Back to cited text no. 5  [PUBMED]  
6.Halloran P, Mathew T, Tomlanovich S, et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. Transplantation 1997; 63(1):39-47.  Back to cited text no. 6    
7.Bjarnason I. Enteric coating of mycophe­nolate sodium: a rational approach to limit topical gastrointestinal lesions and extend the therapeutic index of mycophenolate. Transplant Proc 2001; 33:3238-40.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Schmouder R, Faucharld P, Arns W, et al. Systemic exposure of mycophenolic acid (MPA) is greater with Myofortic TM than with MMF. American Transplant Congress, April 28-May 1, 2002, Washington, USA. Poster No. 380. URL (accessed August 1, 2004): http://www.translantationschweiz. ch/f/myfortic/studien_02.htm  Back to cited text no. 8    
9.Shaw LM, Holt DW, Oellerich M, Meiser B, van Gelder T. Current issues in therapeutic drug monitoring of mycophenolate acid: report of a roundtable discussion. Ther Drug Monit 2001;23:305-15.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Granger DK. Enteric-coated mycophenolate sodium: results of two pivotal global multi­center trials. Transplant Proc 2001;33:3241-4.  Back to cited text no. 10    
11.Knoll G, MacDonald I, Khan A, Van Walraven C. Myco-phenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003;14:2381-6.  Back to cited text no. 11    
12.Pelletier RP, Akin B, et al. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 2003;17:200-5.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Product Monograph. Myofortic® (myco­phenolate sodium). Novartis Pharma, USA, February 2004.  Back to cited text no. 13    
14.Ettenger R, Choi L, Al-Akash S, et al. Single dose pharmacokinetics of enteric­coated mycophenolate sodium in stable pediatric renal transplant recipients: Preliminary results. XIX International Congress of The Transplantation Society. Miami, USA, August 25-30, 2002. URL (accessed August 1, 2004): http://www.translantationschweiz.ch/f/myfortic/studien_08.htm  Back to cited text no. 14    
15.Budde K, Glander P, Diekmann F, et al. Enteric-coated mycophenolate sodium: safe conversion from mycophenolate mofetil in maintenance renal transplant recipients. Transplant Proc 2004;36(2 Suppl):524S-7S.  Back to cited text no. 15    
16.Sollinger H. Enteric-coated mycophenolate sodium: therapeutic equivalence to myco­phenolate mofetil in de novo renal transplant patients. Transplant Proc 2004; 36(2 Suppl):517S-20S.  Back to cited text no. 16    

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Correspondence Address:
Monica Zolezzi
Lecturer in Clinical Pharmacy, University of Auckland, Private Bag 92019, Auckland
NewZealand
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PMID: 18202489

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    Introduction
    An Overview of ECMS
    Clinical Efficac...
    Therapeutic Cons...
    Prescribing Info...
    Comparative Feat...
    Switching Patien...
    Pharmacoeconomic...
    Conclusions
    References
    Article Tables
 

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