Rofecoxib Methotrexate

Methotrexate is often prescribed for the management of rheumatoid arthritis, and some NSAIDs have been reported to interact with it, causing increased plasma methotrexate concentrations, associated with impaired renal function. The safety of concurrent rofecoxib and oral methotrexate has been studied for 3 weeks in 25 patients with rheumatoid arthritis (7). Rofecoxib 12.5-50 mg/day had no effect on the plasma concentrations or renal clearance of methotrexate, but supratherapeutic doses of rofecoxib (75 and 250 mg) caused a significant increase in the plasma methotrexate AUC and reduced its renal clearance. 

Schwartz JI, Agrawal NG, Wong PH, Bachmann KA, Porras AG, Miller JL, Ebel DL, Sack MR, Holmes GB, Redfern JS, Gertz BJ. Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients. J Clin Pharmacol 2001 41(10) 1120-30. 

Clinically important, potentially hazardous interactions with aceclofenac, acetazolamide, acitretin, bendroflumethiazide, benzthiazide, chlorothiazide, chlorthalidone, cocoa, desvenlafaxine, etoricoxib, fluoxetine, guarana, haloperidol, hydrochlorothiazide, hydroflumethiazide, indapamide, insulin detemir, insulin glulisine, meperidine, mesoridazine, methotrexate, methyclothiazide, metolazone, olmesartan, pegfilgrastim, phenylbutazone, polythiazide, quinethazone, rocuronium, rofecoxib, sibutramine, sulpiride, tenoxicam, thiazides, trichlormethiazide, valdecoxib, xipamide, zofenopril, zuclopenthixol... 

Rofecoxib is metabolized in the liver, primarily by cytosolic enzymes, with little renal excretion of unchanged drug. Rofecoxib at 75 mg daily modestly increased methotrexate concentrations, and at 50 mg daily modestly elevated the International Normalized Ratios (INRs) of warfarin patients. Additionally, rifampin can decrease rofecoxib concentrations. Clinically significant interactions were not observed when rofecoxib was administered with crmetidine, digoxin, oral contraceptives, or ketoconazole. Rofecoxib inhibits CYP450 1A2 and may increase serum theophylline area under the curve. 

Rofecoxib 12.5 to 50 mg once daily had no effect on the AUC and renal clearance of methotrexate or 7-hydroxymethotrexate in 19 patients taking methotrexate 7.5 to 20 mg once weekly. However, the authors note that in previous evaluations (data on file), higher than therapeutic doses of rofecoxib (75 mg and 250 mg) were associated with a 23% and 40% increase in the AUC of methotrexate, and an 11% and 40% decrease in its renal clearance, respectively. ... 

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