Mycophenolate mofetil adverse effects

Mycophenolate mofetil (CellCept) inhibits DNA and RNA synthesis and has been shown to have a specific lymphocyte antiproliferative effect. Although not FDA approved for this indication, oral mycophenolate mofetil appears effective in the treatment of moderate to severe plaque psoriasis. The usual dose is 500 mg orally four times a day, up to a maximum of 4 g/day. Common adverse effects include GI toxicity (diarrhea, nausea, vomiting), hematologic effects (anemia, neutropenia, thrombocytopenia), and viral and bacterial infections. Lymphoproliferative disease or lymphoma has been reported. 

To evalnate whether mycophenolate mofetil is effective in treating moderate to severe atopic dermatitis, an open pilot stndy was condncted in 10 patients (34). There were no serions adverse effects, bnt one patient had to discon-tinne treatment becanse he developed Herpes simplex retinitis, which resolved after treatment with aciclovir. Althongh there is no direct evidence that mycophenolate mofetil is a major canse of Herpes retinitis, in this patient it seems likely that it was dne to immunosuppression. In contrast, in vivo and in vitro mycophenolate mofetil strongly potentiates the antiherpetic effects of aciclovir, ganciclovir, and penciclovir (35). It is probably therefore enough to give antiviral therapy only when clinical signs of Herpes infection occur. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Meier-Kriesche H-U, Davies NM, Grinyo J, Heading R, Mamelok R, Wijngaard P, Oellerich M, Maes B. (2005) Mycophenolate sodium does not reduce the incidence of GI adverse effects compared with mycophenolate mofetil. Am J Transplant 5 1164. 

Warnings Increased susceptibility to infection and lymphoma Adverse effects on fetal development have been observed in pregnant rats and rabbits—mycophenolate mofetil should not be used in pregnant women and contraception should be used during therapy Neutropenia has been observed... 

Adverse Effects. The primary adverse effects associated with mycophenolate mofetil are blood disorders (anemia, leukopenia, neutropenia) and gastrointestinal problems (abdominal pain, nausea, vomiting, heartburn, diarrhea, constipation).50 Other side effects include chest pain, cough, dyspnea, muscle pain, weakness, and cardiovascular problems (hypertension, arrhythmias). 

In three pivotal clinical trials of mycophenolate mofetil in kidney transplant recipients, adverse effects were in accordance with the known antiproliferative effect of mycophenolate, namely gastrointestinal disorders, leukopenia, and opportunistic infections, in particular cytomegalovirus tissue invasive disease (SED-13, 1130) (SEDA-20,346). Nephrotoxicity was not observed in clinical trials, and renal function significantly improved in six patients converted to mycophenolate for ciclosporin nephrotoxicity (8). 

Patients with inflammatory bowel disease unresponsive to azathioprine or intolerant of it may benefit from mycophenolate mofetil. Of 12 patients so treated, three had minor adverse effects (headache, nausea, arthralgia). Three with ulcerative colitis developed rectal bleeding while taking mycophenolate mofetil. Histological features of the mucosa were highly... 

In 11 patients with orthotopic hver transplants who had adverse effects from ciclosporin or tacrolimus, mycophenolate mofetil monotherapy for 1 year was successful. This was followed by a randomized, controlled trial in 18 patients, of whom nine were given mycophenolate mofetil (23). Five patients completed the 3 month trial. Of these, two had an episode of acute rejection, one after 2 months and one after 3 months, which did not respond to the reintroduction of tacrohmus and intravenous glucocorticoids. One had a glucocorticoid-responsive episode of severe acute rejection after 3 weeks. The other two patients had normal liver function tests after 2 weeks and 2 months respectively, when the trial was stopped. Mycophenolate mofetil allows a reduction of the dose of... 

Mycophenolate mofetil has been compared with azathioprine in combination with ciclosporin and glucocorticoids in 65 children after kidney transplantation (32). The main adverse effects of this treatment were infections of the urinary tract and the upper respiratory tract, abdominal pain, and diarrhea. Opportunistic infections with cytomegalovirus or cytomegalovirus syndrome occurred in 20% within the first 6 months and tissue-invasive cytomegalovirus disease in 3.1%. These results were similar to those in adults. 

The adverse effects of mycophenolate mofetil in children have been reviewed retrospectively in 24 renal transplant patients (mean age 14 years) switched from azathioprine to mycophenolate mofetil a mean of 4.8 years after transplantation (42). The mean dose of mycophenolate mofetil was 560 mg/m. After a mean of 9.6 months, 13 had to discontinue treatment because of adverse effects, namely severe and partially reversible anemia (10 patients, of whom three required transfusions), neutropenia n — 1), and diarrhea n — 2). The anemia was normocytic and normochromic in nine patients, and such a high incidence of severe anemia was unexpected from the available adult data. Although patients who discontinued treatment had a lower pretreatment-calculated creatinine clearance, this was not significant and probably not the major cause of anemia. The author speculated that the anemia resulted from a disproportionately high unbound plasma concentration of mycophenolate mofetil, due to reduced protein binding and impaired renal clearance. 

Butani L, Palmer J, Baluarte HJ, Polinsky MS. Adverse effects of mycophenolate mofetil in pediatric renal transplant recipients with presumed chronic rejection. Transplantation 1999 68(l) 83-6. 

Mycophenolic acid (MPA) was first isolated from the Penicillin glaucum mold. It was first smdied as an antibiotic but later was found to have immunosuppressive properties. Mycophenolate mofetil (MMF) the morpholinoethyl ester of MPA appears to be a specific immunosuppressant for lymphocytes, resulting in fewer adverse effects than azathioprine, making it the preferred agent over azathioprine. 

The addition of mycophenolate mofetil to ciclosporin has been found to reduce the incidence of rejection episodes in kidney transplant patients and it is licensed for combined use. From the studies above, ciclosporin appears to reduce the levels of the active metabolite, mycophenolic acid, and increase the levels of the glucuronide metabolite (which is associated with mycophenolate adverse effects). The UK manufacturers point out that as efficacy studies were conducted in patients using ciclosporin, mycophenolate and corticosteroids, the finding that ciclosporin reduces the mycophenolic acid AUC by 19% to 38% does not affect the recommended dose requirements. They also state that ciclosporin pharmacokinetics are not affected by mycophenolate. However, this is in contrast to the studies... 

Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil aetiology, incidence and management. Drug Saf 2001 24 645 63. 

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