Mycophenolate mofetil interactions

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... 

Most of the interactions with mycophenolate mofetil and enteric-coated MPA are due to reductions in intestinal absorption. Aluminum-, magnesium-, or calcium-containing antacids decrease the peak level and overall exposure of MPA from either of the preparations.11 If a patient requires liquid antacids, they should be administered at least 4 hours before... 

Drug interactions In a randomized, double-blind study, Zenapax or placebo was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and steroids to assess tolerability, pharmacokinetics, and drug interactions. The addition of Zenapax did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The following medications have been administered in clinical trials with Zenapax with no incremental increase in adverse reactions cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. 

Drug interactions No formal drug-drug interaction studies have been conducted. The following medications have been administered in clinical trials with Simulect with no incremental increase in adverse reactions azathioprine, corticosteroids, cyclosporine, mycophenolate mofetil, and muromonab-CD3. 

Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Although the cytochrome P450 system is not involved, some drug interactions still occur. Plasma drug levels are frequently monitored, similar to the calcineurin inhibitors and PSIs. 

Drug Interactions Acyclovir Antacids with magnesium and aluminum hydroxides Cholestyramine Drugs that alter gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation Probenecid... 

The interaction of ciclosporin with mycophenolate mofetil was investigated in 52 renal transplant patients taking triple therapy (ciclosporin, mycophenolate mofetil, and prednisone), who continued taking the same treatment (n = 19) or underwent elective ciclosporin withdrawal (n = 19) or prednisolone withdrawal (n = 14) 6 months after transplantation (275). Median mycophenolate mofetil trough concentrations 3 months later were about two-fold higher in patients who had discontinued ciclosporin compared with patients who continued to take triple therapy and patients who had discontinued prednisone. No clear mechanism readily explains these changes. 

Hubner GI, Eismann R, Sziegoleit W. Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients. Ther Drug Monit 1999 21(5) 536-9. 

See Chap. 87 on solid organ transplantation for a discussion of drug interactions involving mycophenolate mofetil. 

Therapeutic Uses Mycophenolate mofetil is indicated for prophylaxis of transplant rejection, and it typically is used in combination with glucocorticoids and a calcineurin inhibitor, but not with azathioprine. Combined treatment with siroUmus is possible, although potential drug interactions necessitate careful monitoring of drug levels. For renal transplants, 1 g is administered orally or intravenously (over 2 hours) twice daily (2 g/day). A higher dose, 1.5 g twice daily (3 g/day), is recommended for African American renal transplant patients and all cardiac transplant patients. 

Shah J, Juan D, Bullingham R, Wong B, Wong R, Fu C. A single dose drug interaction study of mycophenolate mofetil and acyclovir in normal subjects. J Clin Pharmacol (1994) 34, 1029. 

S3mtex. A single-dose, pharmacokinetic drug interaction study of oral mycophenolate mofetil and oral acyclovir in normal subjects. Data on file, 1994. 

Gimenez F, Foeillet E, Bourdon O, Weller S, Garret C, Bidault R, Singlas E. Evaluation of pharmacokinetic interactions after oral administration of mycophenolate mofetil and valaciclovir or aciclovir to healftiy subjects. Clin Pharmacokinet (2004) 43, 685-92. 

Royer B, Zanetta G, BerardM, Davani S, Tanter Y, Rifle G, Kantelip J-P. A neutropenia suggesting an interaction between valacyclovir and mycophenolate mofetil. Clin Transplant (2003) 17,158-61. 

No clinically relevant interactions have been seen between mycophenolate mofetil and allopurinol. 

Ducray PS, Banken L, Gerber Boutouyrie B, Zandt H. Absence of an interaction between iron and mycophenolate mofetil absorption. BrJ Clin Pharmacol (2006) 62, 492-5. 

A study in patients with rheumatoid arthritis found that the combination of methotrexate and mycophenolate mofetil was well tolerated and there were no pharmacokinetic interactions. There would appear to be no need for dose adjustments if both drugs are given for rheumatoid arthritis. 

Yocum D, Kremer J, Blackburn W, Caldwell J, Furst D, Nunez M, Zuzga J, Zeig S, Gutierrez M, Merrill J, Dumont E, B Leishman. Cellcept (mycophenolate mofetil - MMF) and methotrexate (MTX) safety and pharmacokinetic (PK) interaction study in rheumatoid arthritis patients./irt/rntisR/rewm (1999) 42 (9 Suppl), S83. 

A study in 11 healthy subjects found that norfloxacin 400 mg twice daily reduced the AUC of a single 1-g oral dose of mycophenolate mofetil given two hours after the antibacterial on day 4 by 10%. The AUC of the glucuronide metabolite was also reduced by 10%. When norfloxacin 400 mg twice daily was also given, the AUC of mycophenolate and its glucuronide metabolite were reduced by 33% and 41%, respectively. This interaction was thought to be due to interference of the enterohepatic recirculation of mycophenolate by the antibacterials. There appear to be no further clinical reports of an interaction between these antibacterials and mycophenolate. The changes with norfloxacin alone were modest, and unlikely to be... 

Mycophenolate mofetil An interaction of aciclovir with mycophenolate mofetil has been reported [20 ]. 

Drag-drag interactions Pantoprazole Proton pump inhibitors suppress acid production and thus increase stomach pH, while mycophenolate mofetil is cleaved in the acidic milieu of the stomach. Of 36 patients with autoimmune diseases taking stable mycophenolate mofetil maintenance therapy, 23 took pantoprazole, and 13 patients received no proton pump inhibitors or antacids [98 j. Pantoprazole reduced the AUC of mycophenolate mofetil by 37% and the Cmax by 60%. 

Drug-drug interactions Mycophenolate mofetil In a pharmacokinetic study of telmisartan, valsartan, and candesartan in combination with mycophenolate mofetil in renal transplant patients, telmisartan increased the elimination of mycophenolic acid there was no interaction with valsartan or candesartan [57 ]. It was suggested that this was due to activation by... 

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