Drug Interactions between amoxicillin / clarithromycin / lansoprazole 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.

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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.

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MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

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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.

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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.

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