Mycophenolate mofetil toxicity

Gastrointestinal Gastrointestinal adverse events are among the main limitations of the use of mycophenolate mofetil. Examination of the surface epithelium, lamina propria, and crypts of mucosal intestinal biopsy tissue in 15 multivisceral transplant patients, including stomach, small intestine, and colon, showed neither specific changes that could be associated with mycophenolate mofetil toxicity nor changes that could differentiate mycophenolate mofetil-related toxicity from acute rejection [88 ]. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

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. 

Mycophenolate mofetil (MMF) is converted to mycophenolic acid, the active form of the drug. The active product inhibits cytosine monophosphate dehydrogenase and, secondarily, inhibits T-cell lymphocyte proliferation downstream, it interferes with leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1. MMF s pharmacokinetics and toxicities are discussed in Chapter 55. 

Mycophenolate mofetil reduces the risk of first acute rejection by 50%. Toxicity is minor, but includes bone marrow suppression and gastrointestinal complaints. A higher incidence of CMV disease compared to azathioprine control wxs observed in the clinical trials. Recent registry studies appear to indicate that renal transplant recipients receiving mycophenolate have improved long-term outcomes. 

There was a dry cough in five of 45 patients taking mycophenolate, associated with dyspnea and hypoxia in one patient and asthma exacerbation in another (9). As the symptoms reversed only after mycophenolate mofetil withdrawal, the authors suggested that dry cough and dyspnea should be considered as early symptoms of pulmonary toxicity. 

Skelly MM, Logan RF, Jenkins D, Mahida YR, Hawkey CJ. Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease. Inflamm Bowel Dis 2002 8(2) 93-7. 

Mycophenolate mofetil 500 mg 4 times a day, up to maximum of 4 g/day Gastrointestinal toxicity (diarrhea, nausea, vomiting), hematologic effects (anemia, neutropenia, thrombocytopenia), viral and bacterial infections lymphoproliferative disease or lymphoma can occur... 

The principal toxicities of mycophenolate are gastrointestinal and hematologic. These include leukopenia, diarrhea, and vomiting. There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus. Tacrolimus in combination with mycophenolate mofetil has been associated with devastating viral infections including polyoma nephritis. 

Observational studies In a study of seven patients with lupus nephritis who failed on mycophenolate mofetil monotherapy, toxicity hmited the use of combination therapy with tacrolimus - - mycophenolate mofetil [84 ]. One patient achieved complete renal remission, and three achieved partial remission with reduced proteinuria. Four of seven patients stopped taking combination therapy because of diabetic ketoacidosis (n = 1), pneumonia ( = 1) and muscle pain (n = 2). Four patients had infectious complications, pneumonia (n = 2), herpes zoster (n = l), and septic arthritis ( = 1). There were no severe nephrotoxic adverse reactions, although there was a small increase in serum creatinine in two patients. 

Mycophenolate mofetil (MMF) is an immunosuppressant with less toxicity than AZA. Because it is associated with less leukopenia, MMF has replaced AZA in most protocols for the treatment of solid organ transplants (169). It has been reported as useful in treating ILD associated with collagen vascular disease (I70-I72) and... 

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