General: Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver (commonly used drugs which are also substrates and/or inhibitors for cytochrome P450 2C9 include warfarin, fluoxetine, fluconazole, phenytoin, and tolbutamide). Co-administration of celecoxib with drugs that are known to inhibit 2C9 should be done with caution as it 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. Furthermore, patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be introduced celecoxib at half the lowest recommended dose, as they may have abnormally high plasma levels due to reduced metabolic clearance. The maximum recommended dose in CYP2C9 poor metabolizers is 100 mg daily.
Concomitant administration of celecoxib with inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates can lead to decreases in plasma concentrations of celecoxib. Therefore, a dose increase of celecoxib may be necessary when celecoxib is co-administered with CYP2C9 inducers.
A clinical pharmacokinetics study and in-vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6. A dose reduction during initiation of celecoxib treatment or a dose increase upon termination of celecoxib treatment may be necessary.
In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.
Acetylsalicylic Acid (ASA) or other NSAIDs: The use of CELEBREX (celecoxib) in addition to any other NSAID, including over-the-counter ones (such as ASA and ibuprofen), for analgesic and/or anti-inflammatory effects is NOT recommended because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.
The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID therapy is associated with additive adverse reactions.
Some NSAIDs (e.g. ibuprofen) may interfere with the anti-platelet effects of low dose ASA, possibly by competing with ASA for access to the active site of cyclooxygenase-1.
As with all other NSAIDs, the concomitant administration of ASA with CELEBREX results in an increased rate of GI ulceration or other complications, compared to use of CELEBREX alone (see CLINICAL TRIALS - Special Studies). In the long-term outcomes study (at 4- and 2-fold the recommended doses for OA and RA, respectively), there was no statistically significant difference for the incidence of complicated ulcers between CELEBREX and comparator groups in patients taking ASA. Concomitant low dose ASA use increased the rate of complicated ulcers to four times that of patients not taking ASA. Resulting incidence rate for complicated ulcers in patients taking CELEBREX and ASA was 1.02%.
Antacids: Co-administration of CELEBREX with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC.
Pharmacokinetic parameters at steady state such as AUC and Cmax for both CELEBREX and omeprazole were comparable when administered alone or together in healthy volunteers (n=36). However increased Gastrointestinal (GI) and skin adverse events such as diarrhoea, abdominal pain, pruritis and rash were observed in combined arm of CELEBREX+omeprazole.
Anticoagulants: Anticoagulation / INR should be monitored in patients taking anticoagulants, particularly in the first few days after initiating or changing CELEBREX therapy, since these patients are at an increased risk of bleeding complications.
The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2-5 mg of warfarin (dose sufficient to prolong prothrombin times to 1.2 to 1.7 times their baseline values). In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, serious bleeding events (some of them fatal) have been reported, predominantly in the elderly, in association with increases in prothrombin time, in patients receiving CELEBREX concurrently with warfarin or similar agents (see ADVERSE REACTIONS - Post-Market Adverse Drug Reactions).
Anti-Hypertensives: NSAIDs may diminish the anti-hypertensive effects of Angiotensin Converting Enzyme (ACE) inhibitors, angiotensin receptor blockers, diuretics and beta blockers. Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics with NSAIDs might result in deterioration of renal function, including increased risk for acute renal failure and hyperkalemia, especially in patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function. Blood pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure.
Lisinopril: In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of celecoxib 200 mg BID resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients co-administered with celecoxib 200 mg BID, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic blood pressure >90 mmHg or cuff diastolic blood pressure increased >10% compared to baseline), compared to 27% of patients co-administered with placebo; this difference was statistically significant.
Anti-platelet Agents: There is an increased risk of bleeding, via inhibition of platelet function, where anti-platelet agents are combined with NSAIDs. CELEBREX does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not appear to inhibit platelet aggregation at indicated dosages (see CLINICAL TRIALS - Special Studies – Platelets and WARNINGS AND PRECAUTIONS – Hematologic – Anti-platelet Effects).
Cyclosporin and Tacrolimus: Although this interaction has not been studied with celecoxib, co-administration of cyclosporin or tacrolimus and any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus due to the NSAID's effect on renal prostaglandins. Renal function should be monitored when celecoxib and either of these drugs is used in combination.
Dextromethorphan and metoprolol: Concomitant administration of celecoxib 200 mg twice daily resulted in a 2.6-fold and a 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib inhibition of metabolism via CYP2D6. Therefore, the dose of dextromethorphan or metoprolol may need to be reduced when treatment with celecoxib is initiated or increased when treatment with celecoxib is terminated.
Digoxin: No interaction data is available for the co-administration of celecoxib and digoxin. However an increase in serum digoxin level has been noted with some NSAIDS.
Diuretics: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the effects of diuretics. This response has been attributed to inhibition of renal prostaglandin synthesis. Although prospective studies of CELEBREX with diuretics have not been conducted, no adverse reactions indicative of elevations in blood pressure were seen in clinical trials in which arthritis patients were taking CELEBREX concurrently with diuretics (n=485). No adverse reactions indicative of sodium retention or renal impairment were seen in clinical trials in patients taking CELEBREX concurrently with diuretics.
Fluconazole: Concomitant administration of fluconazole at 200 mg QD resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics - Metabolism). CELEBREX should be introduced at half the lowest recommended dose in patients receiving fluconazole, with a maximum recommended dose of 100 mg daily.
Glucocorticoids: Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increase the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.
Ketoconazole: CELEBREX did not have a significant effect on the pharmacokinetics of ketoconazole.
Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg BID with CELEBREX 200 mg BID as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn.
Methotrexate: CELEBREX did not have a significant effect on the pharmacokinetics of methotrexate.
Oral contraceptives: In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of a prototype combination oral contraceptive (1 mg norethindrone/ 0.035 mg ethinyl estradiol).
Oral Hypoglycemics: The effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide and tolbutamide has been studied and clinically important interactions have not been found.
Phenytoin: CELEBREX did not have a significant effect on the pharmacokinetics of phenytoin.
Other Drug Interactions: No drug interaction data are available for CELEBREX and the co-administration of the following products: acetaminophen, alcohol, aminoglycosides, bone marrow depressants, butamide, cholestyramine, colchicine, corticosteroids, gold compounds, indapamide, insulin, nephrotoxic agents, nonsteroidal anti-inflammatory agents, potassium supplements, probenecid, valproic acid, zidovudine.
When CELEBREX capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media.
The interaction of CELEBREX with herbal medications or supplements has not been studied.
Drug-Laboratory test Interactions
Interactions with laboratory tests have not been established.