Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving CellCept. Patients should be given complete dosage instructions and informed of the increased risk of lymphoproliferative disease and certain other malignancies. Women of childbearing potential should be instructed of the potential risks during pregnancy, and that they should use effective contraception before beginning CellCept therapy, during therapy, and for 6 weeks after CellCept has been stopped (see WARNINGS and PRECAUTIONS: Pregnancy).
Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, and trimethoprim/sulfamethoxazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. CellCept has not been administered concomitantly with azathioprine.
Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (eg, valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs.
Antacids With Magnesium and Aluminum Hydroxides
Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking MaaloxÒ TC (10 mL qid). The Cmax and AUC(0-24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. CellCept may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that CellCept and the antacid not be administered simultaneously.
Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine. Some degree of enterohepatic recirculation is also anticipated following intravenous administration of CellCept. Therefore, CellCept is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.
Cyclosporine (SandimmuneÒ ) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in 10 stable renal transplant patients. The mean (± SD) AUC(0-12h) and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (± 822) ng· h/mL and 753 (± 161) ng/mL, respectively, compared to 3245 (± 1088) ng· h/mL and 700 (± 246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil. The effect of cyclosporine on mycophenolate mofetil pharmacokinetics could not be evaluated in this study; however, plasma concentrations of MPA were similar to that for healthy volunteers.
Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (± SD) ganciclovir AUC and Cmax (n=10) were 54.3 (± 19.0) m g· h/mL and 11.5 (± 1.8) m g/mL, respectively, after coadministration of the two drugs, compared to 51.0 (± 17.0) m g· h/mL and 10.6 (± 2.0) m g/mL, respectively, after administration of intravenous ganciclovir alone. The mean (± SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (± 21.6) m g· h/mL and 27.8 (± 13.9) m g/mL, respectively, compared to values of 80.3 (± 16.4) m g· h/mL and 30.9 (± 11.2) m g/mL, respectively, after administration of mycophenolate mofetil alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (eg, valganciclovir) are coadministered, patients should be monitored carefully.
A study of coadministration of CellCept (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual cycles. Mean AUC(0-24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0-24h) significantly decreased by about 15%. There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol. Mean serum levels of LH, FSH and progesterone were not significantly affected. CellCept may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. However, it is recommended that oral contraceptives are coadministered with CellCept with caution and additional birth control methods be considered.
Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of MPA was observed. The mean (± SD) AUC and Cmax of MPA after concomitant administration were 75.2 (± 19.8) m g· h/mL and 34.0 (± 6.6) m g/mL, respectively, compared to 79.2 (± 27.9) m g· h/mL and 34.2 (± 10.7) m g/mL, respectively, after administration of mycophenolate mofetil alone.
The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma MPA AUC. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion.
Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption.
During treatment with CellCept, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective . Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Allergic reactions to CellCept have been observed; therefore, CellCept is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. CellCept Intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).