Drug Interaction Report

MONITOR: Chronic administration of antacids may reduce serum salicylate concentrations in patients receiving large doses of aspirin or other salicylates. The mechanism involves reduction in salicylate renal tubular reabsorption due to urinary alkalinization by antacids, resulting in increased renal salicylate clearance. In three children treated with large doses of aspirin for rheumatic fever, serum salicylate levels declined 30% to 70% during coadministration with a magnesium and aluminum hydroxide antacid. Other studies have found similar, albeit less dramatic results. Antacids reportedly have no effect on the oral bioavailability of aspirin in healthy adults. However, administration of antacids containing either aluminum and magnesium hydroxide or calcium carbonate two hours before aspirin dosing led to reduced absorption of aspirin in uremic patients.

MANAGEMENT: Patients treated chronically with antacids (or oral medications that contain antacids such as didanosine buffered tablets or pediatric oral solution) and large doses of salicylates (i.e. 3 g/day or more) should be monitored for potentially diminished or inadequate analgesic and anti-inflammatory effects, and the salicylate dosage adjusted if necessary.

MONITOR: Chronic administration of antacids may reduce serum salicylate concentrations in patients receiving large doses of aspirin or other salicylates. The mechanism involves reduction in salicylate renal tubular reabsorption due to urinary alkalinization by antacids, resulting in increased renal salicylate clearance. In three children treated with large doses of aspirin for rheumatic fever, serum salicylate levels declined 30% to 70% during coadministration with a magnesium and aluminum hydroxide antacid. Other studies have found similar, albeit less dramatic results. Antacids reportedly have no effect on the oral bioavailability of aspirin in healthy adults. However, administration of antacids containing either aluminum and magnesium hydroxide or calcium carbonate two hours before aspirin dosing led to reduced absorption of aspirin in uremic patients.

MANAGEMENT: Patients treated chronically with antacids (or oral medications that contain antacids such as didanosine buffered tablets or pediatric oral solution) and large doses of salicylates (i.e. 3 g/day or more) should be monitored for potentially diminished or inadequate analgesic and anti-inflammatory effects, and the salicylate dosage adjusted if necessary.

MONITOR: Chronic administration of antacids may reduce serum salicylate concentrations in patients receiving large doses of aspirin or other salicylates. The mechanism involves reduction in salicylate renal tubular reabsorption due to urinary alkalinization by antacids, resulting in increased renal salicylate clearance. In three children treated with large doses of aspirin for rheumatic fever, serum salicylate levels declined 30% to 70% during coadministration with a magnesium and aluminum hydroxide antacid. Other studies have found similar, albeit less dramatic results. Antacids reportedly have no effect on the oral bioavailability of aspirin in healthy adults. However, administration of antacids containing either aluminum and magnesium hydroxide or calcium carbonate two hours before aspirin dosing led to reduced absorption of aspirin in uremic patients.

MANAGEMENT: Patients treated chronically with antacids (or oral medications that contain antacids such as didanosine buffered tablets or pediatric oral solution) and large doses of salicylates (i.e. 3 g/day or more) should be monitored for potentially diminished or inadequate analgesic and anti-inflammatory effects, and the salicylate dosage adjusted if necessary.

MONITOR: Coadministration with aluminum-magnesium hydroxide may increase tacrolimus blood concentrations in vivo. The mechanism of interaction is unknown. In a single-dose study, administration of tacrolimus with aluminum-magnesium hydroxide in healthy volunteers resulted in a 10% and 21% increase in tacrolimus peak concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration without aluminum-magnesium hydroxide. This finding contradicts the results from an in vitro study, which showed that tacrolimus incubated in 100 mL simulated gastric fluid with the equivalent of 500 mg of various antacids resulted in loss of tacrolimus, due presumably to a pH-mediated degradation of tacrolimus. Specifically, Mylanta caused a 14% loss of tacrolimus in 24 hours, magnesium oxide caused a 98% loss in 12 hours, and calcium carbonate caused a 30% loss in 24 hours. In contrast, aluminum hydroxide gel caused an immediate 35% loss of tacrolimus (within 2 minutes) and no further loss for 24 hours, suggesting adsorption of tacrolimus.

MANAGEMENT: Given the narrow therapeutic index and the large interindividual variability in the pharmacokinetics of tacrolimus, caution is advised if the drug is used in combination with aluminum and/or magnesium hydroxide. Pharmacologic response and tacrolimus blood levels should be monitored more closely whenever aluminum/magnesium hydroxide is added to or discontinued from therapy, and the immunosuppressant dosage adjusted as necessary. Patients should be advised to contact their doctor if they experience potential signs and symptoms of tacrolimus toxicity such as fever, infection, diarrhea, tremor, headache, fatigue, lethargy, and changes in motor function, mental status, or sensory function.

MONITOR: Coadministration with aluminum-magnesium hydroxide may increase tacrolimus blood concentrations in vivo. The mechanism of interaction is unknown. In a single-dose study, administration of tacrolimus with aluminum-magnesium hydroxide in healthy volunteers resulted in a 10% and 21% increase in tacrolimus peak concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration without aluminum-magnesium hydroxide. This finding contradicts the results from an in vitro study, which showed that tacrolimus incubated in 100 mL simulated gastric fluid with the equivalent of 500 mg of various antacids resulted in loss of tacrolimus, due presumably to a pH-mediated degradation of tacrolimus. Specifically, Mylanta caused a 14% loss of tacrolimus in 24 hours, magnesium oxide caused a 98% loss in 12 hours, and calcium carbonate caused a 30% loss in 24 hours. In contrast, aluminum hydroxide gel caused an immediate 35% loss of tacrolimus (within 2 minutes) and no further loss for 24 hours, suggesting adsorption of tacrolimus.

MANAGEMENT: Given the narrow therapeutic index and the large interindividual variability in the pharmacokinetics of tacrolimus, caution is advised if the drug is used in combination with aluminum and/or magnesium hydroxide. Pharmacologic response and tacrolimus blood levels should be monitored more closely whenever aluminum/magnesium hydroxide is added to or discontinued from therapy, and the immunosuppressant dosage adjusted as necessary. Patients should be advised to contact their doctor if they experience potential signs and symptoms of tacrolimus toxicity such as fever, infection, diarrhea, tremor, headache, fatigue, lethargy, and changes in motor function, mental status, or sensory function.

In vitro data suggest that the presence of antacids may reduce the bioavailability of tacrolimus. An in vitro study showed that tacrolimus incubated in 100 mL simulated gastric fluid with the equivalent of 500 mg of various antacids resulted in loss of tacrolimus, due presumably to a pH-mediated degradation of tacrolimus. Specifically, aluminum-magnesium hydroxide caused a 14% loss of tacrolimus in 24 hours, magnesium oxide caused a 98% loss in 12 hours, and calcium carbonate caused a 30% loss in 24 hours. In contrast, aluminum hydroxide gel caused an immediate 35% loss of tacrolimus (within 2 minutes) and no further loss for 24 hours, suggesting adsorption of tacrolimus. Whether these effects occur in vivo, and to what extent, are unknown. Sodium bicarbonate has been reported to cause widely variable trough plasma levels and reduced blood concentrations of tacrolimus when given close to the time of administration of tacrolimus. No other details were available in the report. However, in a single-dose study, administration of tacrolimus with aluminum-magnesium hydroxide in healthy volunteers resulted in a 10% and 21% increase (not decrease) in tacrolimus peak concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration without aluminum-magnesium hydroxide.

GENERALLY AVOID: The concomitant administration of aluminum-containing products (e.g., antacids and phosphate binders) and citrates may significantly increase serum aluminum concentrations, resulting in toxicity. Citrates or citric acid are contained in numerous soft drinks, citrus fruits, juices, and effervescent and dispersible drug formulations. Citrates enhance the gastrointestinal absorption of aluminum by an unknown mechanism, which may involve the formation of a soluble aluminum-citrate complex. Various studies have reported that citrate increases aluminum absorption by 4.6- to 50-fold in healthy subjects. Patients with renal insufficiency are particularly at risk of developing hyperaluminemia and encephalopathy. Fatalities have been reported. Patients with renal failure or on hemodialysis may also be at risk from soft drinks and effervescent and dispersible drug formulations that contain citrates or citric acid. It is unknown what effect citrus fruits or juices would have on aluminum absorption in healthy patients.

MANAGEMENT: The concomitant use of aluminum- and citrate-containing products and foods should be avoided by renally impaired patients. Hemodialysis patients should especially be cautioned about effervescent and dispersible over-the-counter remedies and soft drinks. Some experts also recommend that healthy patients should separate doses of aluminum-containing antacids and citrates by 2 to 3 hours.

ADJUST DOSING INTERVAL: The administration of aluminum-containing antacids with enteral nutrition may result in precipitation, formation of bezoars, and obstruction of feeding tubes. The proposed mechanism is the formation of an insoluble complex between the aluminum and the protein in the enteral feeding. Several cases of esophageal plugs and nasogastric tube obstructions have been reported in patients receiving high-protein liquids and an aluminum hydroxide-magnesium hydroxide antacid or an aluminum hydroxide antacid.

MANAGEMENT: Some experts recommend that antacids should not be mixed with or given after high protein formulations, that the antacid dose should be separated from the feeding by as much as possible, and that the tube should be thoroughly flushed before administration.

ADJUST DOSING INTERVAL: Administration with food may increase the absorption of calcium. However, foods high in oxalic acid (spinach or rhubarb), or phytic acid (bran and whole grains) may decrease calcium absorption.

MANAGEMENT: Calcium may be administered with food to increase absorption. Consider withholding calcium administration for at least 2 hours before or after consuming foods high in oxalic acid or phytic acid.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.