Drug Interactions between amoxicillin / clarithromycin / omeprazole and mycophenolate mofetil

MONITOR CLOSELY: Antibiotics which affect beta-glucuronidase producing bacteria in the intestine (e.g., aminoglycosides, cephalosporins, fluoroquinolones, and penicillins) may reduce systemic exposure to mycophenolic acid (MPA) products. The exact mechanism is not known; but is thought to be due to interference with enterohepatic recirculation of the active drug, MPA, via alterations in the gastrointestinal flora that are responsible for regenerating MPA from its glucuronide metabolite. One study reviewed 64 kidney transplant patients taking mycophenolate mofetil (MMF) who received either oral ciprofloxacin (500 mg twice daily for 7 days) or amoxicillin plus clavulanic acid (375 mg three times daily for at least 14 days). This study demonstrated approximately 50% reductions in the median trough MPA concentrations from baseline (MMF alone) in 3 days following the start of oral ciprofloxacin or amoxicillin plus clavulanic acid. The reductions in trough MPA concentrations tended to diminish within 14 days of antimicrobial therapy and cease within 3 days of the discontinuation of antibiotics. It is important to note that the trough level may not accurately reflect changes in the overall MPA exposure as the systemic exposure (AUC) was not evaluated in this study. In a study of 11 healthy volunteers who received a single-dose of MMF 1 gram on day 4 of a 5-day course of dual antibiotic therapy with both norfloxacin and metronidazole, the average AUC of MPA was reduced by 33% compared to the administration of MMF alone. However, when MMF was administered with norfloxacin alone or metronidazole alone (as opposed to the combination of MMF with norfloxacin and metronidazole), the reduction in AUC was not statistically significant. In a study of 12 healthy male volunteers, a single dose of MMF 1.5 grams was administered on day 8 of a 10-day course of trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily and no effect on the bioavailability of MPA was observed.

MANAGEMENT: Close clinical and laboratory monitoring for evidence of diminished immunosuppressive effects of mycophenolic acid products is recommended during concomitant therapy and shortly after antibiotic treatment is completed. Advise patients to report any symptoms of transplant rejection such as a decrease in organ function (e.g., reduced urine output for kidney transplant patients, shortness of breath and/or swelling in heart transplant patients, jaundice in liver transplant patients), and/or flu-like symptoms.

MONITOR CLOSELY: Antibiotics which affect beta-glucuronidase producing bacteria in the intestine (e.g., aminoglycosides, cephalosporins, fluoroquinolones, and penicillins) may reduce systemic exposure to mycophenolic acid (MPA) products. The exact mechanism is not known; but is thought to be due to interference with enterohepatic recirculation of the active drug, MPA, via alterations in the gastrointestinal flora that are responsible for regenerating MPA from its glucuronide metabolite. One study reviewed 64 kidney transplant patients taking mycophenolate mofetil (MMF) who received either oral ciprofloxacin (500 mg twice daily for 7 days) or amoxicillin plus clavulanic acid (375 mg three times daily for at least 14 days). This study demonstrated approximately 50% reductions in the median trough MPA concentrations from baseline (MMF alone) in 3 days following the start of oral ciprofloxacin or amoxicillin plus clavulanic acid. The reductions in trough MPA concentrations tended to diminish within 14 days of antimicrobial therapy and cease within 3 days of the discontinuation of antibiotics. It is important to note that the trough level may not accurately reflect changes in the overall MPA exposure as the systemic exposure (AUC) was not evaluated in this study. In a study of 11 healthy volunteers who received a single-dose of MMF 1 gram on day 4 of a 5-day course of dual antibiotic therapy with both norfloxacin and metronidazole, the average AUC of MPA was reduced by 33% compared to the administration of MMF alone. However, when MMF was administered with norfloxacin alone or metronidazole alone (as opposed to the combination of MMF with norfloxacin and metronidazole), the reduction in AUC was not statistically significant. In a study of 12 healthy male volunteers, a single dose of MMF 1.5 grams was administered on day 8 of a 10-day course of trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily and no effect on the bioavailability of MPA was observed.

MANAGEMENT: Close clinical and laboratory monitoring for evidence of diminished immunosuppressive effects of mycophenolic acid products is recommended during concomitant therapy and shortly after antibiotic treatment is completed. Advise patients to report any symptoms of transplant rejection such as a decrease in organ function (e.g., reduced urine output for kidney transplant patients, shortness of breath and/or swelling in heart transplant patients, jaundice in liver transplant patients), and/or flu-like symptoms.

MONITOR: Coadministration with inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) may reduce the bioavailability of mycophenolic acid (MPA) from the administration of mycophenolate mofetil. The exact mechanism of interaction has not been established, but may involve a decrease in MPA solubility at higher gastric pH levels. When single doses of proton pump inhibitors were given to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil, MPA peak plasma concentration (Cmax) was reduced by 30% to 70% and systemic exposure (AUC) by 25% to 35%. The clinical significance is unknown. The interaction does not appear to occur when mycophenolic acid itself is administered. In 12 healthy volunteers, the pharmacokinetics of MPA were observed to be similar when a single 720 mg dose of mycophenolic acid was administered alone and following concomitant administration with pantoprazole, which was administered at a dosage of 40 mg twice daily for 4 days.

MANAGEMENT: Because clinical relevance of this interaction has not been established, PPIs or PCABs should be used with caution in transplant patients receiving mycophenolate mofetil.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.