Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed (see section 4.4).

Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists.
Therefore, the combination should be administered with caution, especially in the elderly.
Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
Acetylsalicylic Acid: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily).
Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant administration of low-dose acetylsalicylic acid with etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone.
Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended (see sections 5.1 and 4.4.).

Cyclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib, coadministration of cyclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when etoricoxib and either of these drugs is used in combination.

Pharmacokinetic interactions
The effect of etoricoxib on the pharmacokinetics of other drugs

Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.

Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate monitoring for methotrexate-related toxicity is recommended when etoricoxib and methotrexate are administered concomitantly.

Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive concomitantly or separated by 12 hours, increased the steady state AUC0-24hr of EE by 50 to 60%. This increase in EE concentration should be considered when selecting an oral contraceptive for use with etoricoxib. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g., venous thrombo-embolic events in women at risk).

Hormone Replacement Therapy (HRT): Administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg PREMARINTM) for 28 days, increased the mean steady state AUC0-24hr of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%). The effect of the recommended chronic doses of etoricoxib (30, 60, and 90 mg) has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC0-24hr) to these estrogenic components of PREMARIN were less than half of those observed when PREMARIN was administered alone and the dose was increased from 0.625 to 1.25 mg. The clinical significance of these increases is unknown, and higher doses of PREMARIN were not studied in combination with etoricoxib. These increases in estrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with etoricoxib because the increase in oestrogen exposure might increase the risk of adverse events associated with HRT.

Prednisone/prednisolone: In drug-interaction studies, etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone.
Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin Cmax (approximately 33%). This increase is not generally important for most patients. However, patients at high risk of digoxin toxicity should be monitored for this when etoricoxib and digoxin are administered concomitantly.

Effect of etoricoxib on drugs metabolised by sulfotransferases
Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has been shown to increase the serum concentrations of ethinyl estradiol. While knowledge about effects of multiple sulfotransferases is presently limited and the clinical consequences for many drugs are still being examined, it may be prudent to exercise care when administering etoricoxib concurrently with other drugs primarily metabolised by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolised by CYP isoenzymes
Based on in vitro studies, etoricoxib is not expected to inhibit cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin breath test.

Effects of other drugs on the pharmacokinetics of etoricoxib
The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles have not been studied in vivo.

Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers, did not have any clinically important effect on the single- dose pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).


Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical miconazole oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in exposure to etoricoxib, but is not considered to be clinically meaningful based on published data.


Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction may result in recurrence of symptoms when etoricoxib is co-administered with rifampicin.
While this information may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended (see section 4.2).

Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant extent.