Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.

Effects of esomeprazole on the pharmacokinetics of other medicinal products As esomeprazole is one enantiomer of omeprazole it is reasonable to advise about interactions reported with omeprazole.

Protease inhibitors
Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP2C19.

For atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax, and Cmin).
Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once a day) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg once a day without omeprazole 20 mg once a day. Co-administration of omeprazole (40 mg once a day) reduced mean nelfinavir AUC, Cmax, and Cmin by 36 - 39 % and mean AUC, Cmax, and Cmin for the pharmacologically active metabolite M8 was reduced by 75 - 92%. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated (see section 4.3 and 4.4).

For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg once a day). Treatment with omeprazole 20 mg once a day had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir).
Treatment with esomeprazole 20 mg once a day had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg once a day had no effect on the exposure of lopinavir (with concomitant ritonavir).

Methotrexate
When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.

Tacrolimus
Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and the dose of tacrolimus adjusted if needed.

Medicinal products with pH dependent absorption
Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. The absorption of medicinal products taken orally such as ketoconazole, itraconazole and erlotinib can decrease during treatment with esomeprazole and the absorption of digoxin can increase during treatment with esomeprazole.

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic monitoring of digoxin should then be reinforced.

Medicinal products metabolised by CYP2C19
Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as warfarin, phenytoin, citalopram, imipramine, clomipramine, diazepam, etc., the plasma concentrations of these medicinal products may be increased and a dose reduction could be needed. In case of clopidogrel, a prodrug which is transformed into its active metabolite via CYP2C19, the plasma concentrations of the active metabolite may be decreased.

Warfarin
Concomitant administration of 40 mg esomeprazole to warfarin-treated patients in a clinical study showed that coagulation times were within the accepted range. However, post-marketing, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.

Clopidogrel
Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and 
esomeprazole (40 mg orally daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%.

In a study in healthy subjects, there was a decreased exposure by almost 40% of the active metabolite of clopidogrel when a fixed dose combination of esomeprazole 20 mg + acetylsalicylic acid 81 mg was given with clopidogrel compared to clopidogrel alone. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in both groups.

Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.

Phenytoin
Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

Voriconazole
Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUCτ by 15% and 41%, respectively.

Cilostazol
Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and
26% respectively, and one of its active metabolites by 29% and 69% respectively.

Cisapride
In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life(t1/2) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole.

Diazepam
Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.

Investigated medicinal products with no clinically relevant interaction Amoxicillin and quinidine Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin and quinidine.

Naproxen or rofecoxib
Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Effects of other medicinal products on the pharmacokinetics of esomeprazole Medicinal products which inhibit CYP2C19 and/or CYP3A4
Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg twice a day (b.i.d.)), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCt by 280%. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Medicinal products which induce CYP2C19 and/or CYP3A4
Medicinal products known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St.
John’s wort (Hypericum perforatum)) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.