Drug Interactions between acetaminophen / aluminum hydroxide / aspirin / caffeine / magnesium hydroxide and Naproxen Sodium DS

GENERALLY AVOID: The antiplatelet and cardioprotective effect of low-dose aspirin may be antagonized by coadministration of some nonsteroidal anti-inflammatory drugs (NSAIDs). Ibuprofen has been specifically implicated, and there is evidence that others including indomethacin, naproxen, and tiaprofenic acid may also interact. The mechanism is competitive inhibition of platelet cyclooxygenase by certain NSAIDs, which, unlike aspirin, bind reversibly at the active site of the enzyme and cause a temporary rather than persistent depression of thromboxane formation and thromboxane-dependent platelet function. Unpublished single-dose trials with ibuprofen 400 mg indicate that interference with aspirin's antiplatelet activity, as measured by thromboxane B2 (TXB2) levels and platelet activation studies, occurs when ibuprofen is taken within 8 hours before or 30 minutes after dosing of immediate-release aspirin. One study showed that the antiplatelet effect of enteric-coated low-dose aspirin is attenuated when ibuprofen 400 mg is dosed 2, 7, and 12 hours after aspirin. In contrast, a placebo-controlled study found no clinically significant reduction of TXB2 inhibition when ibuprofen (400 mg three times a day) was coadministered with chewable, immediate-release aspirin (81 mg once a day) for 10 days in healthy volunteers. There are no clinical endpoint studies conducted specifically to evaluate the interaction. A retrospective study of 7107 heart patients discharged from hospitals between 1989 and 1997 with aspirin prescriptions found that those also taking ibuprofen were twice as likely to die during the study period as those taking aspirin alone or with other NSAIDs or acetaminophen. That translates to 12 extra deaths (3 heart-related deaths) a year for every 1000 patients treated. A subgroup analysis from a 5-year randomized, double-blind, placebo-controlled trial of 325 mg aspirin use on alternate days among 22,071 apparently healthy U.S. male physicians with prospective observational data on use of NSAIDs found that regular (>= 60 days/year) but not intermittent (1 to 59 days/year) use of NSAIDs inhibited the clinical benefits of aspirin on first myocardial infarction (MI). Specifically, regular users of NSAIDs in the aspirin group had a greater than 2-fold increased risk of MI, while regular users of NSAIDs in the placebo group had a nonsignificantly reduced risk of MI. There was no association between intermittent use of NSAIDs and subsequent development of MI among aspirin or placebo recipients.

MONITOR: The combined use of aspirin with NSAIDs in general may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. Pharmacokinetically, aspirin at anti-inflammatory dosages or higher has been shown to decrease the plasma concentrations of many NSAIDs, including indomethacin and naproxen.

MANAGEMENT: Until more information is available, patients receiving low-dose aspirin for cardioprotection should avoid the regular use of NSAIDs including ibuprofen, indomethacin, naproxen, and tiaprofenic acid. Occasional, single use may be acceptable, as the risk from any attenuation of the antiplatelet effect of low-dose aspirin is likely to be minimal given the long-lasting effect of aspirin on platelets. If routine NSAID therapy is necessary, diclofenac may be a viable alternative. In the retrospective study implicating ibuprofen, 75 mg twice daily of delayed-release diclofenac did not interfere with the antiplatelet activity of aspirin. Other noninterfering alternatives for pain include acetaminophen, celecoxib, or narcotic analgesics. In any case, caution is advised whenever aspirin is combined with a NSAID due to the potential for additive GI toxicity. Patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as abdominal pain, bloating, sudden dizziness or lightheadedness, nausea, vomiting, hematemesis, anorexia, and melena.

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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.

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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.

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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.

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Antacids and some oral aluminum, calcium, or magnesium containing preparations 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) produced by antacids. In patients treated with antacids, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered. Concomitant use of these drugs is generally not recommended. Aluminum hydroxide and some magnesium-containing antacids have also been reported to reduce the absorption of regular naproxen. The interaction may be minimized by separating the times of administration by at least 2 hours.

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Antacids and some oral aluminum, calcium, or magnesium containing preparations 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) produced by antacids. In patients treated with antacids, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered. Concomitant use of these drugs is generally not recommended. Aluminum hydroxide and some magnesium-containing antacids have also been reported to reduce the absorption of regular naproxen. The interaction may be minimized by separating the times of administration by at least 2 hours.

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