Drug Interactions between bismuth subcitrate potassium and lansoprazole / naproxen

GENERALLY AVOID: Theoretically, proton pump inhibitors may decrease the gastrointestinal absorption of enteric-coated naproxen, which requires an acidic environment for dissolution. The proposed mechanism is an increase in gastric pH (i.e. decreased gastric acidity) induced by proton pump inhibitors. In patients treated with proton pump inhibitors, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered.

MANAGEMENT: Concomitant use of these drugs is generally not recommended.

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.