Acyclovir: Higher MPAG (the phenolic glucuronide of MPA) and acyclovir plasma concentrations were observed when mycophenolate mofetil was administered with acyclovir than when the drugs were administered alone. 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, e.g. valacyclovir to compete for tubular secretion, further increasing the concentrations of both drugs.
Antacids and proton pump inhibitors (PPIs): Decreased mycophenolic acid (MPA) exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole were administered with CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept patients not taking PPIs, no significant differences were seen. This data support extrapolation of this finding to all antacids because the reduction in exposure when CellCept was co-administered with magnesium and aluminium hydroxides is considerably lower than when CellCept was co-administered with PPIs.
Cholestyramine: Following single-dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pretreated with 4 g three times daily of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA. Caution should be used during concomitant administration of drugs that interfere with enterohepatic circulation (see Precautions).
Cyclosporin A: Cyclosporin A (CsA) pharmacokinetics were unaffected by mycophenolate mofetil. However CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30-50% in renal transplant patients treated with CellCept and CsA compared with patients receiving sirolimus or belatacept and similar doses of Cellcept. Conversely, changes of MPA exposure should be expected when switching patients from CsA to one of the immunosuppressants which do not interfere with MPA's enterohepatic cycle (see Precautions).
Drugs affecting glucuronidation: Concomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure (e.g., increase of MPA AUC0-∞ by 35% was observed with concomitant administration of isavuconazole). Caution is therefore recommended when administering these drugs concomitantly with CellCept.
Telmisartan: Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of mycophenolic acid (MPA) concentrations. Telmisartan changes MPA's elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression which in turn results in an enhanced UGT1A9 expression and activity. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between CellCept patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic DDI were seen. However, caution should be exercised when CellCept is co-administered with telmisartan and monitoring of CellCept levels may be considered.
Ganciclovir: Based on the results of a single-dose administration study of recommended doses of oral mycophenolate and iv ganciclovir and the known effects of renal impairment on the pharmacokinetics of mycophenolate mofetil (see Pharmacology: Pharmacokinetics under Actions and Precautions) and ganciclovir, it is anticipated that coadministration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and mycophenolate mofetil dose adjustment is not required. In patients with renal impairment in which mycophenolate mofetil and ganciclovir or its prodrugs, e.g. valganciclovir are coadministered, patients should be monitored carefully.
Oral contraceptives: A study of coadministration of CellCept (1g twice daily ) and combined oral contraceptives containing ethinylestradiol (0.02 - 0.04 mg) and levonorgestrel (0.05 - 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 - 0.10 mg) conducted in 18 women with psoriasis over 3 menstrual cycles showed no clinically relevant influence of CellCept on serum levels of progesterone, LH and FSH, thus indicating no influence of CellCept on the ovulation-suppressing action of the oral contraceptives. The pharmacokinetics of oral contraceptives were not affected to a clinically relevant degree by coadministration of CellCept (see Females and Males of Reproductive Potential under Precautions).
Rifampicin: After correction for dose a 70% decrease in MPA exposure (AUC0-12h) has been observed with concomitant rifampicin administration in a single heart-lung transplant patient. It is therefore recommended to monitor MPA exposure levels and to adjust CellCept doses accordingly to maintain clinical efficacy when the drugs are administered concomitantly.
Tacrolimus: Exposure to tacrolimus concomitantly administered with CellCept had no effect on the AUC or Cmax of MPA in liver transplant recipients. A similar finding was observed in a recent study in kidney transplant recipients.
In renal transplant patients it was shown that the tacrolimus concentration did not appear to be altered by CellCept.
However, in hepatic transplant patients, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of CellCept (1.5 g twice daily.) were administered to patients taking tacrolimus.
Antibiotics eliminating β-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antibiotics) may interfere with MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure (see Interactions under Precautions).
Information concerning the following antibiotics is available: Ciprofloxacin or amoxicillin plus clavulanic acid: Reductions in pre-dose (trough) MPA concentrations of 54% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. Effects tended to diminish with continued antibiotic use and cease after discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure, therefore clinical relevance of these observations is unclear.
Norfloxacin and metronidazole: Norfloxacin in combination with metronidazole reduced the MPA AUC0- 48 by 30% following a single dose of CellCept. No such effect on the systemic exposure of MPA with either of these antibiotics occurred when they were administered separately.
Other interactions: Co-administration of probenecid with mycophenolate mofetil in monkeys raises the plasma AUC of MPAG 3-fold. 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.
Concomitant administration of sevelamer and CellCept in adults and pediatric patients decreased the MPA Cmax and AUC0-12 by 30% and 25 %, respectively. This data suggest that sevelamer and other calcium free phosphate binders preferentially should be given 2 hours after CellCept intake to minimise the impact on the absorption of MPA.
Live vaccines: live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see Precautions).