Meloxicam has clinically significant interactions with multiple drugs, primarily increasing risks of bleeding, renal injury, and attenuated antihypertensive effects. Close monitoring is required during concomitant use, especially in elderly patients and those with renal impairment.

Drugs that interfere with hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs)

Meloxicam and anticoagulants (e.g., warfarin) have additive effects on bleeding, and the risk of serious bleeding with combined use is higher than with either agent alone. Platelet-derived serotonin plays an important role in hemostasis; case-control and cohort studies suggest that concomitant use of SSRIs/SNRIs with NSAIDs may further increase bleeding risk. Monitor for signs of bleeding closely during combined therapy.

Aspirin

Concomitant use of NSAIDs with analgesic-dose aspirin does not increase efficacy but significantly increases gastrointestinal adverse effects. Coadministration with low-dose aspirin (for cardioprotection) also increases the risk of gastrointestinal bleeding. Routine concomitant use of analgesic-dose aspirin is not recommended. If low-dose aspirin is required, closely monitor for gastrointestinal bleeding. Xifyrm cannot substitute for low-dose aspirin for cardiovascular protection.

ACE inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers

NSAIDs may attenuate the antihypertensive effects of ACEIs, ARBs, or beta-blockers. In elderly patients, those with volume depletion (including those on diuretic therapy), or those with renal impairment, coadministration with ACEIs/ARBs may lead to worsening renal function, even acute renal failure. Monitor blood pressure during combined therapy to ensure target achievement; in elderly, volume-depleted, or renally impaired patients, monitor for signs of renal deterioration, ensure adequate hydration, and assess renal function at baseline and periodically thereafter.

Diuretics

NSAIDs can reduce the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics, attributed to NSAID inhibition of renal prostaglandin synthesis. However, studies show that multiple-dose meloxicam does not attenuate the natriuretic effect or pharmacokinetics of furosemide. During combined therapy, monitor for signs of renal deterioration and ensure adequate diuretic effect (including blood pressure control).

Lithium

NSAIDs can increase plasma lithium concentrations (mean increase of 15%) and reduce renal lithium clearance (mean reduction of about 20%), attributed to NSAID inhibition of renal prostaglandin synthesis. Monitor for signs of lithium toxicity during combined therapy.

Methotrexate

Coadministration may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Monitor for methotrexate toxicity during combined therapy.

Cyclosporine

Coadministration may increase cyclosporine nephrotoxicity. Monitor for signs of renal deterioration during combined therapy.

NSAIDs and salicylates

Concomitant use with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of gastrointestinal toxicity without significant increase in efficacy. Concurrent use is not recommended.

Pemetrexed

Coadministration may increase pemetrexed-related myelosuppression, renal, and gastrointestinal toxicity. In patients with renal impairment (CrCl 45-79 mL/min), monitor for these toxicities when used together. Meloxicam should be withheld for 5 days before, on the day of, and for 2 days after pemetrexed administration. Coadministration is not recommended in patients with CrCl<45 mL/min.

CYP2C9 inhibitors

CYP2C9 is the major metabolizing enzyme for meloxicam; CYP2C9 inhibitors (e.g., amiodarone, fluconazole, sulfaphenazole) may reduce metabolic clearance, leading to abnormally elevated meloxicam plasma concentrations. Consider dose reduction when coadministering with CYP2C9 inhibitors and monitor for adverse effects.