Rofecoxib Warfarin

Another COX-2-selective non-steroidal antiinflammatory drug, rofecoxib, increased plasma concentrations of the biologically less active isomer, R(+) warfarin, which accounted for an approximately 8% increase in INR at steady state in healthy volunteers (33). 

Standard monitoring of INR in patients taking warfarin should be performed when therapy with celecoxib or rofecoxib is begun or changed. 

Significant increases in International Normalized Ratio (INR) have been reported in patients who took rofecoxib and warfarin in some, the increase in INR was accompanied by a bleeding event (8,9). Careful monitoring of the INR in patients taking warfarin and concomitant rofecoxib is mandatory. 

Anonymous. Interaction of rofecoxib with warfarin. Aust Adv Drug React Bull 2002 21 3. 

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. 

Etoricoxib, lumiracoxib and rofecoxib caused a slight 8% to 15% increase in the INR in response to warfarin, whereas celecoxib and parecoxib had no effect. However, raised INRs accompanied by bleeding, particularly in the elderly, have been attributed to the use of waHarin and celecoxib or rofecoxib in other reports. In addition, in a case-control study in patients taking warfarin, the use of celecoxib or rofecoxib was associated with an increased risk of hospitalisation for upper gastrointestinal haemorrhage, which was of a similar magnitude to that seen with non-selective NSAIDs. 

However, in 16 patients stabilised on warfarin and given celecoxib 200 mg daily for 3 weeks, the INR increased by 13%, 6% and 5% at week 1, 2 and 3, respectively, the change at week 1 being statistically significant. In another analysis, of 28 patients taking warfarin who were prescribed either celecoxib or rofecoxib, 13 had increases in their INR, of which 7 (5 taking celecoxib) had no other explanation for the INR increase... 

Moreover, in a ease-control study, patients taking warfarin and admitted to hospital with an upper gastrointestinal haemorrhage were signifi-eantly more likely to be also taking rofecoxib (odds ratio 2.4)2 Note that rofeeoxib has generally been withdrawn because of adverse cardiovascular effects. 

Rofecoxib possibly inhibits the metabolism of the less active R-warfarin via inhibition of CYP1A2, and the active R-acenocoumarol by the same isoenzyme and CYP2C19. ... 

Schaefer MG, Plowman BK, Morreale AP, Egan M. Interaction of rofecoxib and celecoxib with warfarin. Am J Health-Syst Pharm (2003) 60, 1319-23. 

Schwartz JI, Bugianesi KJ, Ebel DL, De Smet M, Haesen R, Larson PJ, Ko A, Verbesselt R, HuntTL, LinsR, Lens S, Porras AG, Dieck J, KeymeulenB, GertzBJ. The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin. Clin Pharmacol Ther ( 000) 68, 626-36. 

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