Drug Interaction Report

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.

MONITOR: Coadministration with proton pump inhibitors or H2-receptor antagonists may significantly increase the gastrointestinal absorption of bismuth from bismuth subcitrate potassium (also known as colloidal bismuth subcitrate or tripotassium dicitratobismuthate), a process that appears to be dependent on intragastric pH. In a study conducted in six healthy volunteers, administration of omeprazole 40 mg/day orally for 1 week increased mean bismuth peak plasma concentration (Cmax) and systemic exposure (AUC) from a single 240 mg dose of bismuth subcitrate potassium by 136% and 274%, respectively, compared to placebo. The magnitude of these changes correlated with the degree of hypochlorhydria. The study also reported that plasma levels of bismuth were sometimes briefly over the "toxic" threshold of 100 mcg/L, although the clinical relevance of this observation following more prolonged dosing is uncertain. In another study conducted in 12 healthy volunteers, ranitidine 300 mg given orally for two doses 9 hours apart increased the median bismuth Cmax and 8-hour AUC from a single 240 mg dose of bismuth subcitrate potassium by 95% and 141%, respectively, compared to placebo. These increases were not caused by changes in renal bismuth clearance. By contrast, pretreatment with ranitidine had no significant effects on plasma bismuth exposures from single doses of bismuth subsalicylate and bismuth subnitrate, with very little systemic absorption of bismuth either with or without ranitidine pretreatment despite both formulations containing considerable amounts of bismuth. Previous studies have also reported on the limited systemic absorption of bismuth from these salts. When Pylera (a treatment preparation for Helicobacter pylori infection that contains bismuth subcitrate potassium 420 mg, metronidazole 375 mg, and tetracycline 375 mg per recommended dose) was administered four times daily with omeprazole 20 mg orally twice daily for 6 days in 34 healthy volunteers, mean bismuth Cmax and AUC increased by 215% and 191%, respectively, compared to administration without omeprazole. Concentration-dependent neurotoxicity has been associated with long-term use of bismuth; however, it is unlikely to occur with short-term administration or steady-state blood concentrations below 50 ng/mL. In the study, one subject transiently achieved a bismuth Cmax higher than 50 ng/mL (73 ng/mL) following multiple dosing of Pylera with omeprazole but did not exhibit symptoms of neurotoxicity. According to the manufacturer, there is no clinical evidence to suggest that short-term exposure to bismuth Cmax concentrations above 50 ng/mL is associated with neurotoxicity.

MANAGEMENT: Caution is advised when bismuth subcitrate potassium is used concomitantly with proton pump inhibitors or H2-receptor antagonists. Since food is known to impair the gastrointestinal absorption of bismuth, some authorities recommend taking this combination with food to minimize the potential risk of bismuth toxicity. Additionally, the increased gastric retention time of bismuth in the presence of food may be clinically beneficial, as it likely prolongs the exposure of Helicobacter pylori to high concentrations of bismuth.

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.

ADJUST DOSING INTERVAL: Food may impair the gastrointestinal absorption and decrease the bioavailability of bismuth from the administration of bismuth subcitrate potassium (also known as colloidal bismuth subcitrate or tripotassium dicitratobismuthate). The clinical significance of this effect is unknown, as the relative importance of systemic versus local bismuth concentrations for antimicrobial activity against Helicobacter pylori has not been established. Investigators have suggested that the increased gastric retention time of bismuth in the presence of food may be beneficial by prolonging the local exposure of Helicobacter pylori to high concentrations of bismuth, although the amount of bismuth absorbed systemically and secreted back into the gastric fluid may also contribute to its therapeutic effect. When Pylera (a treatment preparation for Helicobacter pylori infection that contains bismuth subcitrate potassium 420 mg, metronidazole 375 mg, and tetracycline 375 mg per recommended dose) was administered after a standardized high-fat breakfast in 23 healthy volunteers, mean systemic exposure (AUC) for bismuth decreased by 60% compared to administration in the fasting state. Metronidazole and tetracycline AUC values were also reduced by 6% and 34%, respectively. However, these changes are not deemed clinically relevant, as eradication rates of Helicobacter pylori near 90% have been reported in trial patients administered Pylera routinely after meals.

MANAGEMENT: Pylera and generic equivalents should be administered after meals (breakfast, lunch, and dinner) and at bedtime (preferably with a snack). The manufacturers for some of the other bismuth subcitrate potassium products have recommended avoiding the ingestion of food, beverages, or other medications within one-half hour before and after each dose. The prescribing information or package labeling should be consulted for dosing and administration instructions that are appropriate for each product.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.