Indomethacin Drug Interactions: What to Avoid and What to Tell Your Doctor

Indomethacin has a number of clinically significant drug interactions — some that require you to avoid the combination entirely, and others that require close monitoring. Before starting indomethacin, give your doctor and pharmacist a complete list of every medication, supplement, and herbal product you take. This guide covers the most important interactions you need to know.

Interactions to Avoid Completely

Other NSAIDs and Ketorolac

Do not take indomethacin with other NSAIDs (ibuprofen, naproxen, diclofenac, ketorolac, aspirin, celecoxib, meloxicam, etc.). Combining NSAIDs increases the risk of GI bleeding, ulcers, and kidney damage without providing meaningful additional benefit. Ketorolac is specifically contraindicated with indomethacin due to additive toxicity. This includes both prescription and over-the-counter NSAIDs.

High-Dose Methotrexate

Indomethacin reduces renal clearance of methotrexate, causing methotrexate levels to build up in the body. At high doses used for cancer treatment, this interaction can be fatal — causing severe hematologic toxicity (bone marrow suppression) and GI toxicity. If you are on high-dose methotrexate for cancer treatment, indomethacin should generally be avoided. At low doses used for rheumatoid arthritis, the interaction is lower-risk but still warrants close monitoring.

Interactions Requiring Caution and Monitoring

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Blood Thinners (Anticoagulants)

Warfarin (Coumadin), dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and enoxaparin all carry increased bleeding risk when combined with indomethacin. NSAIDs irritate the stomach lining AND have an antiplatelet effect — when combined with blood thinners, the risk of serious GI bleeding is significantly higher than with either drug alone. If you must take both, close INR monitoring (for warfarin) and GI protective therapy (a proton pump inhibitor) are recommended.

ACE Inhibitors and ARBs (Blood Pressure Medications)

Indomethacin reduces the production of vasodilating prostaglandins in the kidneys. This can blunt the blood pressure-lowering effect of ACE inhibitors (captopril, lisinopril, enalapril, ramipril) and angiotensin receptor blockers (valsartan, losartan, irbesartan). This combination can also cause a significant decrease in kidney function, particularly in elderly patients, those with pre-existing kidney disease, or those who are dehydrated. If you take both, your blood pressure and kidney function should be monitored.

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Lithium

Indomethacin can significantly increase lithium blood levels by reducing renal lithium excretion. Lithium has a narrow therapeutic window — small increases in blood levels can cause toxicity. Signs of lithium toxicity include tremor, confusion, increased urination, thirst, nausea, and in severe cases, seizures or cardiac arrhythmia. If you take lithium, your doctor will need to monitor lithium levels closely if indomethacin is added to your regimen.

Diuretics (Water Pills)

Indomethacin can reduce the diuretic effect of both loop diuretics (furosemide/Lasix) and thiazide diuretics (hydrochlorothiazide, chlorothiazide) by inhibiting renal prostaglandins that support their action. This can lead to fluid retention and increased blood pressure. If you depend on diuretics for heart failure or hypertension management, this is a clinically important interaction. Your doctor may need to adjust your diuretic dose.

Corticosteroids

Combining indomethacin with oral corticosteroids (prednisone, methylprednisolone, dexamethasone) significantly increases the risk of GI ulcers and bleeding. If you take steroids, your doctor may recommend a proton pump inhibitor (like omeprazole or pantoprazole) to protect your stomach, or may recommend using only one of these medications at a time.

SSRIs and SNRIs (Antidepressants)

Selective serotonin reuptake inhibitors (SSRIs like sertraline, fluoxetine, paroxetine) and SNRIs reduce platelet activation by depleting serotonin in platelets. When combined with an NSAID like indomethacin, this platelet effect is additive, increasing the risk of bleeding — particularly GI bleeding. This interaction is often underappreciated. If you take an SSRI or SNRI, be particularly careful about using indomethacin long-term.

Probenecid

Probenecid (commonly used for gout) can increase indomethacin plasma levels by inhibiting its tubular secretion and biliary excretion. This may enhance both the therapeutic effects and the side effects of indomethacin. Your doctor should be aware if you take both, and may need to use a lower indomethacin dose.

Alcohol

Alcohol and NSAIDs are a risky combination. Both alcohol and indomethacin irritate the stomach lining and impair the stomach's protective mechanisms. The combination significantly increases the risk of GI bleeding, especially with regular alcohol use. Avoid alcohol while taking indomethacin.

Key Takeaway: Tell Your Doctor About Everything

Before starting indomethacin, give your prescriber a complete list of all medications — prescription, OTC, and supplements. This includes aspirin, ibuprofen, naproxen (even OTC doses), blood pressure medications, blood thinners, antidepressants, and herbal products. Your pharmacist can also run a drug interaction check when you fill your prescription. For a companion guide on what side effects to watch for, see Indomethacin side effects: what to expect.