Drug Interactions between acetaminophen / aspirin and ibuprofen

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 Unpublished single-dose trials with ibuprofen 400 mg indicate that interference with aspirin's antiplatelet activity, as measured by thromboxane B2 (TXB2) levels and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 CLOSELY: 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 ibuprofen. One study reported a mean 56% reduction in ibuprofen levels during coadministration of aspirin in seven rheumatoid arthritis patients. No change in the elimination half-life of ibuprofen was observed, which suggests an effect on absorption or protein binding of ibuprofen rather than excretion.

MANAGEMENT: Patients receiving low-dose aspirin for cardioprotection should avoid the regular use of ibuprofen and possibly other NSAIDs. Occasional use of ibuprofen is 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. In patients receiving immediate-release (not enteric-coated) aspirin, single doses of ibuprofen 400 mg may be used but should not be administered within 8 hours before or 30 minutes after the aspirin dose. There are currently no specific recommendations regarding the dosing and timing of single-dose ibuprofen in patients receiving enteric-coated low-dose aspirin. For patients requiring routine NSAID therapy with concomitant low-dose aspirin, 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. Some authorities consider the concomitant use of aspirin with other NSAIDs, including ibuprofen, to be contraindicated due to the potential for additive adverse reactions (AU). However, other authorities restrict the contraindication to the concomitant use of aspirin at analgesic doses (i.e., above 75 mg daily) (UK). 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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