Monoamine Oxidase-A Inhibitors: The use of TREXIMET in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY: Drug Interactions and CONTRAINDICATIONS). MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. In patients taking MAO-A inhibitors, sumatriptan plasma levels attained after treatment with recommended doses are 7-fold higher following oral administration than those obtained under other conditions.

Ergot-Containing Drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (e.g., dihydroergotamine, methysergide) and TREXIMET within 24 hours of each other should be avoided (see CONTRAINDICATIONS).

Methotrexate: Caution should be used if TREXIMET is administered concomitantly with methotrexate. Naproxen sodium and other NSAIDs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly increasing the toxicity of methotrexate. Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.

Aspirin: When naproxen is administered with aspirin, its protein binding is reduced, although the clearance of free naproxen is not altered. The clinical significance of this interaction is not known; however, as with other NSAID-containing products, concomitant administration of TREXIMET and aspirin is not generally recommended because of the potential of increased adverse effects.

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs and triptans (see WARNINGS: Serotonin Syndrome).

Angiotensin-Converting Enzyme Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. The use of TREXIMET in patients who are receiving ACE inhibitors may potentiate renal disease states (see WARNINGS: Renal Effects).

Furosemide: Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy.

Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when TREXIMET and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity.

Probenecid: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.

Propranolol and Other Beta-Blockers: Propranolol 80 mg given twice daily had no significant effect on sumatriptan pharmacokinetics. Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other beta-blockers.

Warfarin: The effects of warfarin and NSAIDs on gastrointestinal bleeding are synergistic, such that patients taking both drugs have a higher risk of serious gastrointestinal bleeding than patients taking either drug alone.