Rofecoxib drug interactions

List of drug interactions
General ACE-inhibitors Aspirin Cimetidine Digoxin Furosemide Ketoconazole Lithium Methotrexate Prednisone/prednisolone Oral Contraceptives Rifampin Warfarin

General
In human studies the potential for rofecoxib to inhibit or induce CYP 3A4 activity was investigated in studies using the intravenous erythromycin breath test and the oral midazolam test. No significant difference in erythromycin demethylation was observed with rofecoxib (75 mg daily) compared to placebo, indicating no induction of hepatic CYP 3A4. A 30% reduction of the AUC of midazolam was observed with rofecoxib (25 mg daily). This reduction is most likely due to increased first pass metabolism through induction of intestinal CYP 3A4 by rofecoxib. In vitro studies in rat hepatocytes also suggest that rofecoxib might be a mild inducer for CYP 3A4. Return to top

ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors. In patients with mild to moderate hypertension, administration of 25 mg daily of VIOXX with the ACE inhibitor benazepril, 10 to 40 mg for 4 weeks, was associated with an average increase in mean arterial pressure of about 3 mm Hg compared to ACE inhibitor alone. This interaction should be given consideration in patients taking VIOXX concomitantly with ACE-inhibitors. Return to top

Aspirin
Concomitant administration of low-dose aspirin with VIOXX may result in an increased rate of GI ulceration or other complications, compared to use of VIOXX alone. At steady state, VIOXX 50 mg once daily had no effect on the anti-platelet activity of low-dose (81 mg once daily) aspirin, as assessed by ex vivo platelet aggregation and serum TXB2 generation in clotting blood. VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. Return to top

Cimetidine
Co-administration with high doses of cimetidine [800 mg twice daily] increased the Cmax of rofecoxib by 21%, the AUC0-120hr by 23% and the t1/2 by 15%. These small changes are not clinically significant and no dose adjustment is necessary. Return to top

Digoxin
Rofecoxib 75 mg once daily for 11 days does not alter the plasma concentration profile or renal elimination of digoxin after a single 0.5 mg oral dose. Return to top

Furosemide
Clinical studies, as well as post marketing 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. Return to top

Ketoconazole
Ketoconazole 400 mg daily did not have any clinically important effect on the pharmacokinetics of rofecoxib. Return to top

Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. Thus, when VIOXX and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Return to top

Methotrexate
VIOXX 75 mg administered once daily for 10 days increased plasma concentrations by 23% as measured by AUC0-24 hr in patients receiving methotrexate 7.5 to 15 mg/week for rheumatoid arthritis. An equivalent magnitude of reduction in methotrexate renal clearance was observed. At 24 hours postdose, a similar proportion of patients treated with methotrexate alone (94%) and subsequently treated with methotrexate co-administered with 75 mg of rofecoxib (88%) had methotrexate plasma concentrations below the measurable limit (5 ng/mL). The effects of the recommended doses for osteoarthritis (12.5 and 25 mg) of VIOXX on plasma methotrexate levels are unknown. Standard monitoring of methotrexate-related toxicity should be continued if VIOXX and methotrexate are administered concomitantly. Return to top

Oral Contraceptives
Rofecoxib did not have any clinically important effect on the pharmacokinetics of ethinyl estradiol and norethindrone. Return to top

Prednisone/prednisolone
Rofecoxib did not have any clinically important effect on the pharmacokinetics of prednisolone or prednisone. Return to top

Rifampin
Co-administration of VIOXX with rifampin 600mg daily, a potent inducer of hepatic metabolism, produced an approximate 50% decrease in rofecoxib plasma concentrations. Therefore, a starting daily dose of 25 mg of VIOXX should be considered for the treatment of osteoarthritis when VIOXX is co-administered with potent inducers of hepatic metabolism. Return to top

Warfarin
Prothrombin time (measured as INR) increased in both single and multiple dose cross-over studies in healthy individuals receiving both warfarin and rofecoxib. In a 21 day multiple dose study in healthy individuals stabilized on warfarin (2 to 8.5 mg daily), administration of rofecoxib 25 mg QD was associated with mean increases in INR of approximately 8% (range of INR on warfarin alone, 1.1 to 2.2; range of INR on warfarin plus rofecoxib, 1.2 to 2.4). Return to top