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Indication
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1. Interference with antiretroviral drug therapy It is not recommended to use proton pump inhibitors in combination with atazanavir and nelfinavir. It is expected that the combination with proton pump inhibitors may lead to a significant decrease in the blood concentration of atazanavir, and may lose its efficacy and develop drug resistance. It is expected that the combination with proton pump inhibitors may increase the concentration of saquinavir (often used in combination with atazanavir), resulting in increased toxicity, so the dosage needs to be reduced. It has been reported that omeprazole (esomeprazole is its enantiomer) can interact with some antiretroviral drugs, but the clinical significance and mechanism of action of these interactions are not completely clear. During omeprazole treatment, the gastric pH value increases, which can change the absorption of antiretroviral drugs. Other possible interaction mechanisms are through CYP2C19. Reduced concentrations of atazanavir and nelfinavir It has been reported that for some antiretroviral drugs, such as atazanavir and nelfinavir, the blood concentrations of them are reduced when they are used in combination with omeprazole. After multiple administration of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg, once daily), the AUC of nelfinavir and its pharmacologically active metabolite M8 decreased by 36% and 92%, Cmax decreased by 37% and 89%, and Cmin decreased by 39% and 75%, respectively. After multiple administration of atazanavir (400 mg, once daily) and omeprazole (40 mg, once daily, given 2 hours before atazanavir), the AUC of atazanavir decreased by 94%, Cmax decreased by 96%, and Cmin decreased by 95%. Therefore, the combined use of omeprazole with such drugs (such as atazanavir and nelfinavir) is not recommended. Since omeprazole and esomeprazole have similar pharmacodynamic effects and pharmacokinetic characteristics, the combination of esomeprazole and atazanavir is not recommended, and the combination of esomeprazole and nelfinavir is contraindicated. Increased saquinavir concentrations1 Increased plasma concentrations have been reported for other retroviral drugs, such as saquinavir. After multiple doses of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days and omeprazole 40 mg once daily for 11 to 15 days, saquinavir AUC increased by 82%, Cmax increased by 75%, and Cmin increased by 106%. Therefore, clinical and laboratory monitoring of saquinavir toxicity is recommended during co-treatment with this product. For safety reasons, the saquinavir dose should be reduced based on individual patient differences. It has also been reported that some retroviral drugs have no changes in plasma concentrations after combined use with omeprazole. 2. Drugs whose bioavailability is affected by gastric pH Esomeprazole can inhibit gastric acid secretion. Therefore, for drugs whose bioavailability is significantly affected by gastric pH (such as ketoconazole, itraconazole, atazanavir, iron salts and digoxin), esomeprazole can affect their absorption. 3. Effects on liver metabolism/cytochrome P450 pathway Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is unlikely to inhibit CYP1A2, 2A6, 2C9, 2D6, 2E1 and 3A4, and it is expected that the interaction between this product and drugs metabolized by these CYP enzymes will not be clinically relevant. Drug interaction studies have shown that there is no clinically significant interaction between esomeprazole and drugs such as phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. However, post-marketing reports have shown that patients receiving warfarin and esomeprazole co-treatment have changes in prothrombin test results. Increased prothrombin international normalized ratio (INR) and prothrombin time can lead to abnormal bleeding and even death in patients. Therefore, patients receiving proton pump inhibitors and warfarin co-treatment need to be monitored for increases in INR and prothrombin time. Esomeprazole inhibits CYP2C19, which is the main metabolizing enzyme of this product. Therefore, when esomeprazole is co-administered with drugs metabolized by CYP2C19 (such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc.), the plasma concentrations of these drugs may be increased and a dose reduction may be required. This should be considered especially when this product is used for on-demand treatment. The co-administration of 30 mg of this product can reduce the clearance of diazepam metabolized by CYP2C19 by 45%. Co-administration of 40 mg of this product can increase the trough concentration of plasma phenytoin in patients with epilepsy by 13%. Therefore, during phenytoin treatment, when this product is co-administered or discontinued, it is recommended to monitor the blood concentration of phenytoin. Omeprazole 40 mg once daily increased the Cmax and AUCt of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively. Esomeprazole is metabolized by CYP2C19 and CYP3A4. Co-administration of esomeprazole with the CYP3A4 inhibitor clarithromycin (500 mg, twice daily) can double the body's exposure to esomeprazole (AUC). Co-administration of esomeprazole with a co-inhibitor of CYP2C19 and CYP3A4 can more than double the exposure of esomeprazole. Voriconazole, an inhibitor of CYP2C19 and CYP3A4, increased the AUCt of omeprazole by 280%. In the above two situations, the dose of esomeprazole does not need to be routinely adjusted. However, for patients with severe liver damage and those who require long-term treatment, the dose adjustment of this product should be considered. The results of the study of clopidogrel in healthy subjects showed that there was a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg oral daily dose), resulting in an average decrease of 40% in the exposure of clopidogrel's active metabolite, which ultimately led to an average decrease of 14% in the maximum inhibition of platelet aggregation (ADP-induced). In the study of healthy subjects, the exposure of clopidogrel's active metabolite was reduced by almost 40% when clopidogrel was co-administered with a fixed dose of esomeprazole 20 mg and aspirin (ASA) 81 mg compared with clopidogrel alone. However, the maximum inhibition level of platelet aggregation (ADP-induced) was the same in the clopidogrel group and the clopidogrel combination (esomeprazole ASA) group. In both observational and clinical studies, major cardiovascular events caused by the PK/PD interaction of esomeprazole were reported, resulting in data inconsistent with clinical effects. Therefore, in the [Precautions], it is mentioned that simultaneous use with clopidogrel is not encouraged. Omeprazole is an inhibitor of CYP2C19. A crossover study of omeprazole and cilostazol in 20 healthy subjects showed that after one week of continuous administration of omeprazole 40 mg once a day, the Cmax and AUC of cilostazol increased by 18% and 26%, respectively, and the Cmax and AUC of its active metabolite 3,4-dihydro-cilostazol (with an activity 4 to 7 times that of cilostazol) increased by 29% and 69%, respectively. It is expected that the concentration of cilostazol and its above-mentioned active metabolites can be increased after the co-administration of cilostazol and esomeprazole. Therefore, it should be considered to reduce the dose of cilostazol from 100 mg twice a day to 50 mg twice a day. Inducers of CYP2C19 or CYP3A4 or both enzymes (e.g., rifampicin) can result in decreased plasma concentrations of esomeprazole. Interactions have been reported between omeprazole (as its enantiomer) and the CYP3A4 inducer Hypericum perforatum. A crossover study involving 12 healthy male subjects showed that Hypericum perforatum (300 mg, three times daily for 14 days) significantly reduced the systemic exposure of omeprazole in both CYP2C19 slow metabolizers (Cmax and AUC values decreased by 37.5% and 37.9%, respectively) and rapid metabolizers (Cmax and AUC values decreased by 49.6% and 43.9%, respectively). Therefore, co-administration of this product with Hypericum perforatum or rifampicin should be avoided. Short-term studies evaluating the co-administration of esomeprazole with dapoxetine or rofecoxib did not show clinically relevant pharmacokinetic interactions. 4. Interactions between this product and drugs used in neuroendocrine tumor screening Drug-induced reduction of gastric acid can lead to hyperplasia of enterochromaffin-like cells and increased levels of phagochroman A, thus interfering with the screening of neuroendocrine tumors. 5. Tacrolimus The combined use of this product with tacrolimus can lead to increased tacrolimus blood concentrations. 6. Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that the combined use of PPIs and methotrexate (mainly high doses; see methotrexate prescribing information) may increase the serum concentration of methotrexate and/or its metabolites and prolong the duration of high serum concentrations. However, no formal drug interaction studies on methotrexate and PPIs have been conducted. In some patients, it has been reported that methotrexate levels increase when co-administered with PPIs. When high-dose methotrexate is used for treatment, temporary withdrawal of esomeprazole may be considered. [Overdose] Esomeprazole: There is very limited experience with overdose of esomeprazole, and symptoms associated with a dose of 280 mg are gastrointestinal symptoms and weakness. There are no abnormal reactions to a single dose of 80 mg of esomeprazole. There is no known specific antidote. Esomeprazole is extensively bound to plasma proteins and is therefore difficult to dialyze. Symptomatic treatment and systemic supportive therapy should be used for the treatment of any overdose. Sodium bicarbonate: Overdose of sodium bicarbonate may cause electrolyte abnormalities (hypocalcemia, hypokalemia, hypernatremia), metabolic alkalosis, and seizures. Supportive treatment and correction of electrolyte abnormalities should be performed. |
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