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General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Consider starting treatment at half the lowest recommended dose.
Concomitant administration of celecoxib with inhibitors of CYP2C9 can lead to increases in plasma concentrations of celecoxib. Therefore, a dose reduction of celecoxib may be necessary when celecoxib is co-administered with CYP2C9 inhibitors.
Concomitant administration of celecoxib with inducers of CYP2C9, such as rifampicin, carbazepine and barbiturates can lead to decreased in plasma concentrations of celecoxib.
Celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.
Drug-specific: Interaction of celecoxib with warfarin or similar agents: (See Precautions for Use with Oral Anticoagulants).
Lithium: When receiving lithium together with celecoxib, lithium plasma levels increased approximately 17%. Therefore, patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.
Aspirin: Celecoxib does not interfere with the anti-platelet effect of low-dose aspirin. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin in the prophylactic treatment of cardiovascular disease.
Anti-hypertensives including Angiotensin-converting enzyme inhibitors (ACEIs), Angiotensin II antagonist (also known as angiotensin receptor blockers, ARBs), diuretics and beta-blockers: Inhibition of prostaglandins may diminish the effect of anti-hypertensives including (ACEIs), and/or ARBs, diuretics and beta-blockers. This interaction should be given consideration in patients taking celecoxib concomitantly with ACEIs and/or ARBs, diuretics and beta-blockers.
In patients who are elderly, volume depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, angiotensin II antagonists or diuretics, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
Lisinopril: Approximately half of patients who received the ACE inhibitor, lisinopril, in combination with celecoxib were unresponsive to lisinopril at the final clinic visit, compared to under one third of patients who received lisinopril in combination with placebo; and this difference was statistically significant.
Cyclosporine: Because of their effect on renal prostaglandins, NSAIDs may increase the risk of nephrotoxicity with cyclosporine.
Fluconazole and ketoconazole: Since celecoxib is predominantly metabolized by CYP2C9 it should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in celecoxib Cmax of 60% and AUC of 130%. Ketonazole, a CYP3A4 inhibitor, showed no clinically relevant inhibition in the metabolism of celecoxib.
Dextromethorphan and metoprolol: Concomitant administration of celecoxib 200 mg twice daily resulted in a 2.6-fold and 1.5-fold increase in plasma concentration of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib inhibition to the CYP2D6 substrate metabolism via CYP2D6. Therefore, the dose of drugs as CYP2D6 substrate may need to be reduced when treatment with celecoxib is initiated or increased when treatment with celecoxib is terminated.
Diuretics: NSAIDs, in some patients, can reduce the natriuretic effect of furosemide and thiazides by inhibition of renal prostaglandin synthesis.
Methotrexate: No pharmacokinetic interactions have been observed when combining celecoxib and methotrexate.
Oral contraceptives: Celecoxib had no effects on the pharmacokinetics of a prototype combination oral contraceptive (1 mg norethindrone/0.035 mg ethinyl estradiol).
Other drugs: No interactions have been observed with celecoxib and antacids (aluminium and magnesium), omeprazole, glibenclamide (glyburide), phenytoin, or tolbutamine.
