Interaction

Effects of esomeprazole on the pharmacokinetics of other drugs

The decrease in gastric hydrochloric acid secretion during treatment with esomeprazole and other proton pump inhibitors may result in decreased or increased absorption of drugs whose absorption depends on the acidity of the environment. Like other drugs that reduce gastric acidity, treatment with esomeprazole may lead to decreased absorption of ketoconazole, itraconazole and erlotinib, and increased absorption of drugs such as digoxin. Co-administration of omeprazole at a dose of 20 mg once daily and digoxin increased digoxin bioavailability by 10% (digoxin bioavailability was increased by up to 30% in two out of ten patients). Omeprazole has been shown to interact with some antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known. An increase in pH during therapy with omeprazole may affect the absorption of antiretroviral drugs. There may also be an interaction at the level of CYP2C19 isoenzyme. When coadministration of omeprazole and some antiretroviral drugs such as atazanavir and nelfinavir during therapy with omeprazole, a decrease in their serum concentrations is noted. Therefore, their concomitant use is not recommended. The co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers led to a significant decrease of atazanavir bioavailability (area under the “concentration-time curve”, maximum (Cmax) and minimum (Cmin) concentrations decreased by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir bioavailability.

Concomitant use of omeprazole and saquinavir resulted in increased serum concentrations of saquinavir; when used with some other antiretrovirals their concentrations were unchanged. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, co-administration of esomeprazole with antiretrovirals such as atazanavir and nelfinavir is not recommended.

Esomeprazole inhibits CYP2C19, the main isoenzyme involved in its metabolism. Accordingly, co-administration of esomeprazole with other drugs whose metabolism involves the CYP2C19 isoenzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to increased plasma concentrations of these drugs, which in turn may require dose reduction. This interaction is particularly important to keep in mind when using Nexium on an “as needed” regimen. Co-administration of esomeprazole 30 mg and diazepam, which is a substrate of CYP2C19 isoenzyme, decreases diazepam clearance by 45%.

The use of esomeprazole at a dose of 40 mg resulted in a 13% increase in residual phenytoin concentrations in patients with epilepsy. Therefore, it is recommended to monitor plasma concentrations of phenytoin at the beginning of treatment with esomeprazole and at its withdrawal.

The use of omeprazole in dose of 40 mg once daily increased area under curve “concentration – time” and Cmax of voriconazole (substrate of CYP2C19 isoenzyme) by 15% and 41%, respectively.

The co-administration of warfarin with 40 mg of esomeprazole does not alter the coagulation time in patients taking long-term warfarin. However, several cases of clinically significant increases in INR (international normalized ratio) have been reported when warfarin and esomeprazole are coadministered. It is recommended to monitor INR at the beginning and at the end of coadministration of esomeprazole and warfarin or other coumarin derivatives.

In studies, a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg and maintenance dose

75 mg/day) and esomeprazole (40 mg/day. orally), which results in an average 40% decrease in exposure to the active metabolite clopidogrel and an average 14% decrease in maximal inhibition of ADP-induced platelet aggregation.

The clinical significance of this interaction is unclear. In a prospective study in patients receiving placebo or omeprazole at a dose of 20 mg/day concomitantly with clopidogrel and acetylsalicylic acid (ASA) therapy and in an analysis of clinical outcomes of large randomized trials, no increased risk of cardiovascular complications was shown when clopidogrel and proton pump inhibitors including esomeprazole were used together.

The results of several observational studies are inconsistent and do not provide a definitive answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications with clopidogrel and proton pump inhibitors.

When clopidogrel was coadministered with a fixed combination of 20 mg of esomeprazole and 81 mg of ASA, exposure to the active metabolite clopidogrel was reduced by nearly 40% compared with clopidogrel monotherapy, while maximum levels of inhibition of ADP-induced platelet aggregation were similar, which is likely due to the simultaneous administration of low-dose ASA.

The use of omeprazole at a dose of 40 mg resulted in an 18% and 26% increase in Cmax and AUC (area under the concentration-time curve) of cilostazol, respectively; for one of the active metabolites of cilostazol, the increases were 29% and 69%, respectively. Concomitant administration of cisapride with 40 mg of esomeprazole leads to increased values of pharmacokinetic parameters of cisapride in healthy volunteers: AUC – by 32% and elimination half-life – by 31%, but maximum cisapride plasma concentration is not significantly changed. Slight prolongation of the QT interval, which was observed with cisapride monotherapy, was not increased when Nexium was added (see section “Special Precautions”).

Concomitant use of esomeprazole and tacrolimus resulted in increased serum concentrations of tacrolimus.

In some patients, increased concentrations of methotrexate have been noted when coadministered with proton pump inhibitors. If high doses of methotrexate are used, temporary withdrawal of esomeprazole should be considered.

The drug Nexium does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.

Studies evaluating short-term co-administration of esomeprazole and naproxen or rofecoxib have shown no clinically significant pharmacokinetic interaction.

Influence of drugs on the pharmacokinetics of esomeprazole

The CYP2C19 and CYP3A4 isoenzymes are involved in metabolism of esomeprazole. Co-administration of esomeprazole with clarithromycin (500 mg 2 times per day), which inhibits the CYP3A4 isoenzyme, leads to a 2-fold increase in the AUC of esomeprazole. Co-administration of esomeprazole and a combined CYP3A4 and CYP2C19 isoenzyme inhibitor such as voriconazole may lead to more than a 2-fold increase in the AUC of esomeprazole. No dose adjustment of esomeprazole is usually required in such cases. A dose adjustment of esomeprazole may be required in patients with severe hepatic impairment and long-term use.

Drugs inducing CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and preparations of St. John’s wort, when used in combination with esomeprazole may lead to decreased plasma concentration of esomeprazole due to accelerated metabolism of esomeprazole.

Special Instructions

In the presence of any alarming symptoms (such as significant spontaneous weight loss, recurrent vomiting, dysphagia, vomiting with blood or melena) and in the presence of gastric ulcer (or suspected gastric ulcer), malignancy should be excluded, since treatment with Nexium may alleviate symptoms and delay the diagnosis. In rare cases patients taking omeprazole for a long time have revealed atrophic gastritis during histological examination of biopsy specimens of gastric mucosa.
Patients taking the drug for a long period (especially over a year) should be under regular medical supervision.
Patients taking Nexium “as needed” should be instructed to contact their physician if the character of symptoms changes. Taking into account the fluctuations in plasma concentrations of esomeprazole when prescribing therapy “as needed”, the interaction of the drug with other medicinal products should be taken into account (see section “Interaction with other medicinal products”). When prescribing Nexium for eradication of Helicobacter pylori, the possibility of drug interactions for all components of triple therapy should be considered. Clarithromycin is a potent CYP3A4 inhibitor, so when prescribing eradication therapy for patients receiving other drugs metabolized with CYP3A4 (e.g., cisapride), possible contraindications and interactions of clarithromycin with these medicines should be considered.
Nexium tablets contain sucrose, so they are contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption or sugar-isomaltase deficiency.
Pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose of 300 mg and maintenance dose of 75 mg/day) and esomeprazole (40 mg/day orally) has been reported, resulting in an average 40% decrease in exposure to the active metabolite clopidogrel and an average 14% decrease in maximal inhibition of ADP-induced platelet aggregation. Therefore, concomitant use of esomeprazole and clopidogrel should be avoided (see section “Interaction with other medicinal products”).
Some observational studies indicate that therapy with proton pump inhibitors may slightly increase the risk of osteoporosis-related fractures, but in other similar studies no increased risk was noted.
Randomized, double-blind, controlled clinical trials of omeprazole and esomeprazole, including two open-label studies of long-term therapy (more than 12 years), have not confirmed the association of osteoporosis-related fractures with proton pump inhibitors.
Although a causal association of omeprazole/esomeprazole use with osteoporotic fractures has not been established, patients at risk for osteoporosis or osteoporotic fractures should be placed under appropriate clinical observation.

Impact on the ability to drive vehicles and mechanisms
Due to the fact that during therapy with Nexium dizziness, blurred vision and somnolence may be observed, caution should be exercised when driving vehicles and other mechanisms.

Synopsis

Tablets 20 mg: oblong biconvex, light pink color, coated, on one side engraved 20 mG, on the other side – AEH.

Tablets 40 mg: oblong biconvex pink coated tablets, on one side engraved 40 mG, on the other side – AEI.

Contraindications

Hypersensitivity to esomeprazole, substituted benzimidazoles or other ingredients of the drug.
Hereditary intolerance of fructose, glucose-galactose malabsorption or sugar-isomaltase deficiency.
Children under 12 years of age (due to lack of data about efficacy and safety of the drug in this group of patients) and children over 12 years of age for other indications except gastroesophageal reflux disease.
Esomeprazole should not be taken together with atazanavir and nelfinavir (see section “Interaction with other medicinal products”).
With caution – severe renal failure (experience of use is limited).

Side effects

Below are the adverse reactions independent of the drug dosing regimen, observed during clinical trials and during post-marketing use of the drug.
The frequency of adverse reactions is given as the following gradation: very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare (< 1/10000).
Skin and subcutaneous tissue Infrequent: dermatitis, itching, rash, urticaria; Rare: alopecia, photosensitization;
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic

epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders Rarely: arthralgia, myalgia;
Very rare: muscle weakness.

Nervous system Often: headache;
Infrequent: dizziness, paraesthesia, somnolence;
Rare: taste disorder.

Mental disorders Infrequent: insomnia;
Rare: depression, agitation, confusion;
Very rare: hallucinations, aggressive behavior.

Gastrointestinal tract
Often: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting;
Infrequent: Dry mouth;
Rare: stomatitis, gastrointestinal candidiasis;
Very rare: microscopic colitis (confirmed histologically).

Liver and biliary tract
Infrequent: increased activity of “liver” enzymes;
Rare: hepatitis (with or without jaundice;
Very rare: liver failure, encephalopathy in patients with liver disease.

Genital and mammary gland disorders Very rare: gynecomastia.

Blood and lymphatic system Rare: leukopenia, thrombocytopenia;

Very rare: agranulocytosis, pancytopenia.

Immune system disorders
Rare: hypersensitivity reactions (e.g., fever, angioedema, anaphylactic reaction/anaphylactic shock).

Respiratory system, thorax and mediastinum Rare: bronchospasm.

Renal and urinary tract Very rare: interstitial nephritis.

Visual system Rare: blurred vision.

Metabolism and nutrition Infrequent: peripheral edema;
Rare: hyponatremia;
Very rare: hypomagnesemia, hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

General disorders
Rare: malaise, sweating.

Overdose

To date, extremely rare cases of intentional overdose have been described. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and gastrointestinal symptoms. A single administration of 80 mg of Nexium caused no adverse effects. The antidote for esomeprazole is not known. Esomeprazole binds well to plasma proteins, so dialysis is ineffective. In case of overdose, symptomatic and general supportive treatment is necessary.

Pregnancy use

There are currently insufficient data on the use of Nexium during pregnancy. The results of epidemiological studies of omeprazole, which is a racemic mixture, have shown no fetotoxic effects or impairment of fetal development.

Esomeprazole administration to animals showed no direct or indirect adverse effects on fetal or fetal development. Administration of the racemic mixture of the drug also did not have any adverse effects on animals during pregnancy, delivery, and postnatal development.

The drug should be administered to pregnant women only when the expected benefit to the mother outweighs the possible risk to the fetus.

It is not known whether esomeprazole is excreted with the breast milk, so Nexium should not be prescribed while breastfeeding.

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Similarities

Emanera