Mycophenolate mofetil dosing

Mycophenolate mofetil is available in 250 mg capsules and 500 mg tablets, an oral suspension (100 mg/mlL, in cherry syrup), and an injectable.11 Usual doses of mycophenolate mofetil range from 1000 to 3000 mg/day in two to four divided doses. The conversion between oral and IV mycophenolate mofetil is 1 1. Enteric-coated mycophenolic acid is available in 180 and 360 mg tablets. For conversion between mycophenolate mofetil and enteric-coated MPA, 1000 mg mycophenolate mofetil is equivalent to 720 mg enteric-coated MPA.26,29 The recommended starting dose of enteric-coated mycophenolic acid is 720 mg given twice daily.11 It appears that conversion of mycophenolate mofetil to enteric-coated mycophenolic acid is safe, but more studies are needed to determine the exact role of enteric-coated MPA in the immunosuppressive armamentarium. Mycophenolic acid trough concentrations can be monitored, but they are not recommended routinely. 

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... 

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 in doses of 1 to 1.5 g twice daily (maximum dose 3 g/day) is effective as adjunctive therapy in patients with resistant psoriasis on cyclosporine.29,38 As monotherapy, there may be some benefit in patients with moderate psoriasis and psoriatic arthritis, but not in severe psoriasis.29... 

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. 

O fC U Mycophenolate Mofetil Initial dose should be given within 72 hours following transplantation 1.0 g twice a day used in combination with corticosteroids and cyclosporine... 

Combined administration of azathioprine and allopurinol may result in severe pancytopenia. The dose of Azathioprine should be reduced by two-thirds when given with allopurinol. Azathioprine rarely causes liver dysfunction, frequently manifested by an isolated rise in ALT and bilirubin. With the introduction of mycophenolate mofetil, azathioprine may be relegated to a second-line anti metabolite for the prevention of graft rejection. 

The metabolism of mycophenolate is altered by coadministration with cyclosporine. Mycophenolic acid (MPA) levels are lower when mycophenolate mofetil is compared with cyclosporine. Lower doses should be considered in recipients receiving tacrolimus or steroids done without a calcineurin inhibitor. 

Recent data from a kidney pancreas induction study suggests that 2 doses of Daclizumab (2 mg/kg) at day 0 and day 14 is equivalent to 5 doses of 1 mg/kg every 14 days. (Stratta AJ, Alloway RR, Hodge E et al. A multicenter, open-label, comparative trial of two Daclizumab dosing strategies vs. no antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids for the prevention of acute rejection in simultaneous kidney-pancreas transplant recipients interim analysis. Clin Transplant 2002 l6(l) 60-8.)... 

Mycophenolate mofetil is rapidly absorbed after oral administration, and the bioavailability of its oral dose is 94%. It is metabolized by esterases to free MPA, which is the active metabolite. The enterohepatic recirculation plays a crucial role in the serum levels of MPA. The active metabolite is further metabolized by glucuronyl transferase and is eliminated (90%) in urine as the MPA glucuronide (MPAG) as a result of the organic anion transport system in the proximal tubule. A small amount is excreted in feces. 

Azathioprine is administered to patients who do not respond to calcineurin inhibitors, sirolimus and glucocorticoids. Daily doses of 3-10 mg/kg of azathioprine are administered 1 or 2 days before renal transplantation or on the day of surgery for prophylactic therapy. Mycophenolate mofetil is increasingly used in place of azathioprine for tissue transplantation since it is less myelotoxic and causes few opportunistic infections. 

Daclizumab is used for the prophylaxis of acute rejection in patients receiving kidney transplants. A dose of 1 mg/kg is sufficient to completely block all the IL-2 receptors. It is administered in five doses at a 2-week interval where its elimination half-life is about 20 days. A combination of several other immunosuppressive agents including cyclosporine (or tacrolimus, rapamycin), mycophenolate mofetil and corticosteroids can be used with daclizumab. When it is used in combination with tacrolimus, the doses of tacrolimus are reduced. After tissue transplantation, the addition of daclizumab to the standard immunosuppressive regimen produces reduction in tissue rejection up to 50%. Daclizumab can cause hypersensitivity reactions, but it does not cause cytokine-release syndrome. There is a low incidence of... 

SLE appears to be steroid responsive only in the early coiu se of the disease. Optic atrophy occiu s in untreated cases, with the development of permanent visual field defects. Therapy includes high-dose intravenous methyl-prednisolone, oral prednisone, or steroid-sparing medications such as mycophenolate mofetil (CellCept). A rheumatology referral is also advised. 

A 45-year-old woman with a liver transplant began to take mycophenolate mofetil (2 g/day) before planned ciclosporin withdrawal. After 3 days she developed pruritus and a bullous eruption on her hands and feet. The lesions improved after mycophenolate was withdrawn, but soon reappeared after readministration of a lower dose (500 mg/day). A skin biopsy showed dyshidrotic eczema and a skin test with mycophenolate mofetil produced recurrence. 

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... 

The role of mycophenolate in the rate and severity of cjdomegalovirus infection in transplant patients has been debated (SEDA-23, 407) and is difficult to evaluate in otherwise immunosuppressed patients. Whereas there was a dose-related increase in the incidence of cytomegalovirus disease in the three pivotal trials, a later analysis did not confirm that mycophenolate mofetil is specifically associated with an increased risk of cytomegalovirus infection, and suggested that over-immunosuppression rather than mycophenolate mofetil per se was the main contributing factor (SEDA-22, 418) (27-29). 

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. 

Hueso M, Bover J, Seron D, Gil-Vernet S, Sabate I, Fulladosa X, Ramos R, Coll O, Alsina J, Grinyo JM. Low-dose cyclosporine and mycophenolate mofetil in renal allograft recipients with suboptimal renal function. Transplantation 1998 66(12) 1727-31. 

Moreso F, Seron D, Morales JM, Cruzado JM, Gil-Vernet S, Perez JL, FuUadosa X, Andres A, Grinyo JM. Incidence of leirkopettia and cytomegalovirirs disease in kidney trarrsplants treated with mycophenolate mofetil combined with low cyclosporine and steroid doses. Clin Transplant 1998 12(3) 198-205. 

A number of authors report a beneficial effect of CSA dose reduction or discontinuation in conjunction with maintenance or introduction of mycophenolate mofetil (MMF) in patients with histologically proved or clinically suspected chronic CSA nephropathy. Im-... 

Attempts to minimize TAC-induced renal dysfunction by TAC switch to sirolimus [419, 744, 745] or use of low-dose maintenance TAC therapy associated with lymphocyte depleting agents, mycophenolate mofetil or sirolimus have been successfully achieved [746-750]. However, the association of TAC and sirolimus does not seem to be problem-free. Severe acute kidney injury in renal transplant recipients and thrombotic microangiopathy in intestinal transplant have been associated to combined use of TAC and sirolimus [751, 752], renal function improved in renal transplant recipients after conversion from TAC/ sirolimus to TAC/MMF therapy [753] and TAC/sirolimus combination was associated to worst renal allograft survival than TAC/MMF im-... 

Aleksic I, Baryalei M, BuschT, Pieske B, Schorn B, Strauch J, Sirbu El, Dalichau El. Improvement of impaired renal function in heart transplant recipients treated with mycophenolate mofetil and low-dose cyclosporine. Transplantation 2000 69 1586-1590. 

Smak Gregoor PJ,Van GelderT, van BesouwNM, van der Mast BJ, IjzermansJN, Weimar W. Randomized study on the conversion of treatment with cyclosporine to azathioprine or mycophenolate mofetil followed by dose reduction. Transplantation 2000 70 143-148. 

Jain A, Mohanka R, Orloff M, Abt P, Kashyap R, Kelley M, Burlee K, Bozorgzadeh A. Intravenous mycophenolate mofetil with low-dose oral tacrolimus and steroid induction for live donor liver transplantation. Exp Clin Transplant 2005 3 361-365. 

Boyer O, Le Bidois J, Dechaux M, Gubler MC, Niaudet P. Improvement of renal function in pediatric heart transplant recipients treated with low-dose calcineurin inhibitor and mycophenolate mofetil.Transplantation 2005 79 1405-1410. 

Because of the many detrimental effects associated with chronic steroid therapy, dose minimization has been the goal of therapy. The availability of CSA, TAC, and mycophenolate mofetil has permitted complete withdrawal of corticosteroids in some patients. Steroid withdrawal protocols use either a rapid taper of steroids within days of the transplant or a slower taper, whereby patients are weaned gradually from steroids over months to years after transplant. Factors to consider when evaluating smdies of these alternative strategies in transplant patients include patient selection criteria, timing and rapidity of withdrawal, and duration of follow-up. 

Mycophenolate mofetil is usually administered in 500-mg doses four times a day the dosage can be increased up to 4 g/day. 

Mycophenolate mofetil (MMF), an immunosuppressant used in organ transplant, has cleared refractory symptoms of AD in short-term, open-label studies. Since dose finding and weU-controlled studies are not available for MMF use in AD, the agent should be used with caution and discontinued if the patient does not respond within 4 to 8 weeks of therapy. ... 

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