Brand name: Meprezo
International Nonproprietary Name: Esomeprazole
Drug form
Lyophilized powder for intravenous solution preparation
1 bottle contains:
Active substance: Esomeprazole (in a form of Esomeprazole Sodium) - 40 mg.
Pharmacotherapeutic group
Anti-ulcer drugs and gastroesophageal reflux disease (GERD) treatment drugs. Proton pump inhibitors
ATC code A02BC05
Pharmacological properties
Pharmacodynamics
Esomeprazole is the S-isomer of Omeprazole which reduces gastric acid secretion by a specifically directed mechanism of action and the proton pump inhibitor of the gastric mucosa parietal cells. Both the R- and S-isomers of Omeprazole possess similar pharmacodynamic activity.
Mechanism of action
Esomeprazole is a weak alkali, it undergoes concentration and turns into an active form in strongly acidic substance of parietal cells secretory tubules, where it inhibits the H + K + -ATPase enzyme, the proton pump and inhibits basal and stimulated acid secretion.
After 5 days of Esomeprazole oral daily dose of 20 mg or 40 mg therapy an intragastric pH above 4 was maintained for approximately 13-17 hours (dose dependent); in patients with GERD it was established in 24 hours. The effect was achieved equally with oral and intravenous route of administration.
Significant clinical effect of Esomeprazole daily dose of 40 mg in 4 weeks of reflux esophagitis therapy was observed in 78% of patients; in 8 weeks of therapy – in 93%.
After endoscopic hemostasis patients received either 80 mg of Esomeprazole by 30 minutes intravenous infusion followed by continuous infusion of 8 mg/h or placebo for 72 hours. After an initial 72-hour period, all patients were transferred to an open use of Esomeprazole at a dose of 40 mg orally for 27 days to suppress acid secretion. The frequency of repeated bleeding for 3 days was 5.9% in the Esomeprazole group compared to 10.3% in the Placebo group. In 30 days therapy the recurrence rate in the Esomeprazole group compared to the Placebo group was 7.7% and 13.6%, respectively.
The effect of the drugs that suppress hydrochloric acid secretion is associated with an increase in serum gastrin level.
Frequent occurrence of gastric glandular cysts in prolonged treatment with oral antisecretory drugs has been reported. These changes are based on physiological consequence of significant inhibition of hydrochloric acid secretion; they are benign and reversible.
Gastric juice acidity reduction caused by different agents, including proton pump inhibitors, leads to an increase in a number of bacteria usually presented in the gastrointestinal tract. Treatment with proton pump inhibitors can lead to a slight increase in the risk of gastrointestinal infections such as Salmonella and Campylobacter, and in hospitalized patients Clostridium difficile infection is possible.
Pediatric use
In a placebo-controlled study (98 patients aged 1-11 months) efficacy and safety were evaluated in patients with signs and symptoms of GERD. 1 mg/kg of Esomeprazole was administered orally once a day for 2 weeks (open-label phase) and additional 80 patients were included within 4 weeks (double-blind study, treatment phase). There were no significant differences observed between Esomeprazole and Placebo groups at a primary endpoint until the treatment was discontinued due to the symptoms aggravation.
In a placebo-controlled study (52 patients aged <1 month) efficacy and safety were evaluated in patients with GERD symptoms. Esomeprazole at an oral daily dose of 0.5 mg/kg was administered for at least 10 days. There were no significant differences observed between Esomeprazole and Placebo groups at a primary endpoint and changes in initial number of GERD symptoms.
The results of pediatric studies additionally demonstrated that 0.5 mg/kg and 1.0 mg/kg of Esomeprazole used in children aged <1 month and 1 to 11 months old, respectively, reduced an average time period (in percentage) to reach intraesophageal pH <4. The safety profile was similar to that established in adults.
In a study conducted on pediatric patients with GERD (<1 to 17 years old) in prolonged treatment with proton pump inhibitors 61% of children demonstrated insignificant ECL cells hyperplasia, without known clinical significance and without any progression of atrophic gastritis or carcinoid tumors.
Special patients groups
Slow metabolizers
Approximately 2.9 ± 1.5% of the population suffer from deficiency of the functional enzyme CYP2C19 and they are called “slow metabolizers”. In such group of people Esomeprazole metabolism is probably mainly catalyzed by CYP3A4. After repeated Esomeprazole oral dose of 40 mg intake an average total effect was approximately 100% higher in weak metabolizers than in patients with functional CYP2C19 enzyme (extensive metabolizers). Average maximum plasma concentrations increased by approximately 60%. Similar differences were observed in a study with Esomeprazole intravenous administration. These data did not have any effect on Esomeprazole dosage regimen.
Gender
Following an oral Esomeprazole administration at a single dose of 40 mg, an average total effect in women was approximately 30% higher than in men. No differences were observed with a repeated dose once a day. Similar differences were observed in intravenous administration of Esomeprazole. These data did not have any effect on Esomeprazole dosage regimen.
Liver failure
In patients with mild to moderate liver dysfunction Esomeprazole metabolism may be impaired. Metabolic rate in patients with severe liver dysfunction decreases, leading to a doubled total effect of Esomeprazole. Thus, in patients with GERD and severe liver dysfunction maximum dose of 20 mg should not be exceeded. In patients with bleeding ulcers – severe liver failure may be sufficient introduction of an initial bolus dose of 80 mg, followed by continuous intravenous infusion at a dose of 4 mg/h for 71.5 hours. Esomeprazole or its main metabolites do not tend to accumulate when used once a day.
Renal failure
No studies have been conducted on patients with impaired renal function. Since the kidneys are responsible for esomeprazole metabolites excretion but not for the main compound excretion, Esomeprazole metabolism in patients with impaired renal function would not be changed.
Elderly patients
Esomeprazole metabolism in elderly patients (71-80 years).
Pediatric use
In a randomized, open, multinational, repeated dose study Esomeprazole was administered once a day in a form of 3-minute injection for four days. The study included a total of 59 pediatric patients aged 0 to 18, of which 50 patients (7 children aged 1 to 5 yrs.) completed the study and were evaluated for Esomeprazole pharmacokinetics.
The table below describes the systemic effects of Esomeprazole following 3-minute intravenous infusion in pediatric patients and healthy adults. Geometric means (in a range) are presented in the table below. Esomeprazole 20 mg dose was given by a 30 minute infusion for adults. In children CSS, max was measured in 5 minutes following the dose administration and in 7 minutes following 40 mg dose administration – in adults; then – after the final 20 mg dose administration in adults.
|
Age group |
Dose |
AUC ( µmol *h/l) |
Css,max ( µmol /l) |
|
0-1 month * |
0,5 mg/kg (n = 6) |
7,5 (4,5-20,5) |
3,7 (2,7-5,8) |
|
1-11 months * |
1,0 mg/kg (n = 6) |
10,5 (4,5-22,2) |
8,7 (4,5-14,0) |
|
1-5 years |
10 mg (n = 7) |
7,9 (2,9-16,6) |
9,4 (4,4-17,2) |
|
6-11 years |
10 mg (n = 8) |
6,9 (3,5-10,9) |
5,6 (3,1-13,2) |
|
20 mg (n = 8) 20 mg (n = 6) ** |
14,4 (7,2-42,3) 10,1 (7,2-13,7) |
8,8 (3,4-29,4) 8,1 (3,4-29,4) |
|
|
12-17 years |
20 mg (n = 6) |
8,1 (4,7-15,9) |
7,1 (4,8-9,0) |
|
40 mg (n = 8) |
17,6(13,1-19,8) |
10,5 (7,8-14,2) |
|
|
Adults |
20 mg (n = 22) |
5,1 (1,5-11,8) |
3,9 (1,5-6,7) |
|
40 mg (n = 41) |
12,6 (4,8-21,7) |
8,5 (5,4-17,9) |
* A patient from the age group 0 - 1 month was defined as a patient at the age of > 32 full weeks and <44 full weeks, where the adjusted age was the sum of gestational age and postpartum age expressed in full weeks. A patient from the age group 1 to 11 months was at the adjusted age> 44 full weeks.
** Two patients were excluded, 1 of them most likely was a CYP2C19 slow metabolizer and 1 – on combined therapy with a CYP3A4 inhibitor.
Model-based projections have shown that Css, max after Esomeprazole intravenous administration given in a form of 10 minute, 20 minute and 30 minute infusion would be on average lower by 37% - 49%, 54% - 66% and 61% - 72%, in all age and dose groups, respectively, compared with the groups where the dose was given in a form of 3-minute infusion.
Dosage and administration
Adults
Antisecretory therapy, when oral administration is not possible
In patients who cannot take an oral drug form, Meprezo can be given at a parenteral dose of 20-40 mg once a day. In patients with reflux esophagitis the drug should be prescribed at a dose of 40 mg once a day. In patients on symptomatic therapy of reflux disease Meprezo should be prescribed at a dose of 20 mg once a day.
In gastric ulcers associated with NSAID therapy the usual dose is 20 mg once a day. In prevention of gastric and duodenal ulcers associated with NSAID therapy patients at risk should be given 20 mg once a day.
Usually the intravenous treatment duration is short; then, as soon as possible an oral drug administration should be prescribed.
Rebleeding prevention in gastric and duodenal ulcers
In a stomach or duodenal ulcer acute bleeding following therapeutic endoscopy 80 mg of Meprezo should be given in a form of 30 minutes bolus infusion, followed by continuous i/v infusion 8 mg/h for 3 days (72 hours).
Following the parenteral treatment, an oral acid-suppressive therapy should be added.
Solution for Injection preparation
Reconstituted solution: solution for intravenous administration (8 mg/ml) is prepared by adding 5 ml of 0.9% sodium chloride solution for i/v administration into the drug vial. The reconstituted solution should be clear and colorless or slightly yellow.
Dose 40 mg
5 ml of reconstituted solution should be given in a form of i/v injection during at least 3 minutes time period.
Dose 20 mg
2.5 ml or half volume of the reconstituted solution should be given in a form of i/v injection during at least 3 minutes time period. Unused solution residues should be disposed in accordance with the established requirements.
Solution for infusion preparation
Reconstituted solution (dose 40 mg): 1 vial drug contents should be dissolved in 100 ml of 0.9% sodium chloride solution for i/v administration. Reconstituted solution (dose 80 mg): 2 vials drug contents should be dissolved in 100 ml of 0.9% sodium chloride solution for i/v administration.
Dose 40 mg
The reconstituted solution (dose 40 mg) should be used as an intravenous infusion within 10-30 minutes time period.
Dose 20 mg
Half volume of the reconstituted solution (40 mg dose) should be used as i/v infusion within 10-30 minutes time period. Unused solution residues should be disposed in accordance with the established requirements.
Dose 80 mg
The reconstituted solution (80 mg dose) should be used as a continuous i/v infusion within 30 minutes time period.
Dose 8 mg/h
The reconstituted solution (80 mg dose) should be used as a continuous i/v infusion within 71.5 hour time period.
Patients with impaired renal function
In patients with impaired renal function dose adjustment is not required. Due to the limited experience in patients with severe renal failure, Meprezo should be prescribed with caution to such group of patients.
Patients with impaired liver function
GERD: in patients with mild to moderate hepatic insufficiency dose adjustment is not required. In patients with severe hepatic insufficiency the drug maximum daily dose of 20 mg should not be exceeded.
Ulcer bleeding: in patients with mild to moderate hepatic insufficiency dose adjustment is not required. In patients with severe hepatic insufficiency following initial bolus infusion of 80 mg, continuous intravenous infusion at a dose of 4 mg/h for 71.5 hour time period should be prescribed.
Elderly patients
Dose correction is not required in elderly patients.
Pediatric use
Children and adolescents at age 1-18 years old
Antisecretory therapy when oral administration is not possible
In patients who cannot use oral drug form, Meprezo can be administered in a parenteral drug form once a day, in accordance with the recommendations listed in the table below.
Usually, the intravenous treatment duration is short, following oral drug administration – as soon as possible.
|
Recommended Dose for Intravenous (i/v) Esomeprazole administration
Solution for injection preparation
Reconstituted solution: solution for injection (8 mg/ml) is prepared by adding 5 ml of 0.9% sodium chloride solution for i/v administration into the drug vial. The reconstituted solution for injection should be clear and colorless or slightly yellow.
Dose 40 mg
5 ml of reconstituted solution should be used in a form of i/v injection during at least 3 minutes time period.
Dose 20 mg
2.5 ml or half volume of the reconstituted solution should be given in a form of i/v injection during at least 3 minutes! Unused solution residues should be disposed in accordance with the established requirements.
Dose 10 mg
1.25 ml of reconstituted solution should be given in a form of i/v injection during at least 3 minutes. Unused solution residues should be disposed in accordance with the established requirements.
Solution for Infusion preparation
Reconstituted solution: 1 vial drug contents should be dissolved in 100 ml of 0.9% sodium chloride solution for i/v administration. The reconstituted solution should be clear and colorless or slightly yellow.
Dose 40 mg
The reconstituted solution should be given in a form of i/v infusion within a period of 10-30 minutes.
Dose 20 mg
Half volume of the reconstituted solution should be given in a form of continuous i/v infusion within 10-30 minutes. Unused solution residues should be disposed in accordance with the established requirements.
Dose 10 mg
A quarter of the reconstituted solution should be given in a form of continuous i/v infusion within 10-30 minutes. Unused solution residues should be disposed in accordance with the established requirements.
Contraindications
Hypersensitivity to the active substance, substituted Benzimidazoles or any excipient.
Esomeprazole should not be used together with Nelfinavir.
Side effects
Headache, abdominal pain, diarrhea and nausea were the most common reactions in clinical trials (as well as in post-marketing studies). In addition, the safety profile is similar for different formulations, indications for use, age groups and populations. There were no adverse reactions associated with the dosage.
Side effects by frequency of occurrence are classified into the following categories: very often (> 1/10); often (> 1/100 to <1/10); infrequently (> 1/1000 to <1/100); rare (> 1/10,000 to <1/1000); very rare (<1/10000); unknown (frequency cannot be estimated from the data available).
Blood and lymphatic system disorders: rare: leukopenia, thrombocytopenia; very rare: agranulocytosis, pancytopenia.
Immune system disorders: rarely: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
Metabolism and metabolic disorders: infrequently: peripheral edema; rare: hyperlipidemia; unknown: hypomagnesemia (may correlate with hypocalcaemia). Hypomagnesemia may be associated with hypokalemia.
Mental disorders: infrequently: sleeping disorders; rare: agitation, confusion, depression; very rare: aggression, hallucinations.
Nervous system disorders: often: headache; infrequently: dizziness, paresthesia, drowsiness; rare: taste disturbances.
Eye disorders: infrequently: impaired/blurred vision.
Ear and labyrinth disorders: infrequently: vertigo.
Respiratory, thoracic and mediastinal disorders: rare: bronchospasm.
Gastrointestinal tract disorders: often: abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting, stomach polyps (benign); infrequently: dry mouth; rarely: stomatitis, gastrointestinal candidiasis; unknown: microscopic colitis.
Hepatobiliary system disorders: infrequently: liver enzymes increased levels; rare: hepatitis with or without jaundice; very “rare”: liver failure, encephalopathy (in patients with preexisting liver disease).
Skin and subcutaneous tissue diseases: often: allergic reactions at the injection site*; infrequently: dermatitis, purities, rash, urticaria; rare: alopecia, photosensitivity; very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown: subacute cutaneous lupus erythematosis.
Musculoskeletal system and connective tissue disorders: infrequently: hip, wrist and spine fractures; rare: arthralgia, myalgia; very rare: muscle weakness.
Kidney and urinary system disorders: very rare: interstitial nephritis (in some patients, together with renal failure).
Reproductive system and breast disorders: very rare: gynecomastia.
General disorders: rare: malaise, excessive sweating.
* Reactions at the injection site mainly observed in a study with high doses given within 3 days (72 hours) period. In a preclinical study with i/v drug administration vascular irritation was not observed in patients, however, insignificant tissue inflammation reaction was noted in subcutaneous injection site (paravenous). Rreclinical study results indicated that clinical manifestation of tissue irritation was associated with the drug concentration. Irreversible visual impairment was reported in some cases in critically ill patients who received Omeprazole (racemate) in a form of i/v injection, especially at high doses, but no causal relationship was established.
Pediatric use
Randomized, open, multinational study was conducted to evaluate the pharmacokinetics of repeated daily i/v doses given within 4 days period to pediatric patients aged 0 to 18 yrs. A total of 57 patients (8 children aged 1-5 yrs.) were included in the study to evaluate the drug safety profile. The results were consistent with the known safety profile of Esomeprazole and no new safety data had been detected.
Precautionary measures
In case of any alarming symptoms observed (for example, significant weight loss, unintentional recurrent vomiting, dysphagia, hematemesis or melena) as well as with suspected or current gastric ulcer malignant neoplasms should be excluded, as treatment with Esomeprazole can relieve the symptoms and delay the diagnosis.
Gastrointestinal infections
Treatment with proton pump inhibitors may result in a slight increase in the risk of gastrointestinal infections such as Salmonella and Campylobacter.
Vitamin B12 Absorption
Similar to all acid-blockers, Esomeprazole can reduce vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be taken into consideration in patients with reduced body strength or at risk factors presented capable to decrease vitamin B12 absorption in prolonged therapy period.
Hypomagnesemia
Severe hypomagnesemia had been observed in patients treated with proton pump inhibitors (PPIs) for at least three months period and in most cases, for a year. Serious manifestations of hypomagnesemia such as fatigue, tetany, delirium, cramps, dizziness and ventricular arrhythmia may occur, but they may begin spontaneously and might not be noticed in time. Such patients’ condition improved after magnesium replacement therapy and discontinuation of treatment with PPIs. Patients with a long-term planned therapy or those on PPI therapy together with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics) need to monitor magnesium level before and regularly during the treatment.
Subacute cutaneous lupus erythematosis
Treatment with proton pump inhibitors is associated with very rare cases of subacute cutaneous lupus erythematosis. If lesions occur, especially in skin areas exposed to the sun and at concomitant occurrence of arthralgia, the patient should immediately consult a doctor who should consider the possibility of Esomeprazole therapy discontinuation. The occurrence of subacute cutaneous lupus erythematosis at continuous use of Esomeprazole may increase the risk of subacute cutaneous lupus erythematosis observed at the time of other proton pump inhibitors therapy.
Combination with other drugs
Esomeprazole co-administration with Atazanavir is not recommended. In case of necessity to prescribe Atazanavir together with proton pump inhibitors, clinical monitoring is recommended in combination with Atazanavir dose increase to 400 mg and Ritonavir – to 100 mg, while Esomeprazole 20 mg dose should not be exceeded.
Esomeprazole is an inhibitor of СУР2С19. Before and after the treatment with Esomeprazole, the possible interaction with drugs metabolized through СУР2С19 should be evaluated. The interaction has been observed between Clopidogrel and Esomeprazole. Clinical significance of this interaction has not been determined. As a precaution, concomitant use of Esomeprazole and Clopidogrel is not recommended.
Laboratory test results deviations
Elevated level of chromogranin A (CgA) may distort the results of diagnostic tests on neuroendocrine tumors detection. To avoid this situation, proton pump inhibitors therapy should be discontinued at least five days before serum chromogranin levels determination. If CgA and gastrin level did not return to normal values after the initial measurement, chromogranin level determination should be repeated in14 days after proton pump inhibitors therapy discontinuation.
Effects on the ability to drive and operate machinery
Esomeprazole possesses a negligible effect on ability to drive and operate machinery. In cases of adverse reactions such as dizziness and blurred vision occurred, patients on Esomeprazole therapy need to avoid driving and operating machinery.
Pregnancy and lactation
Pregnancy: clinical data on the drug intake during pregnancy are insufficient. Animal studies have not shown any direct or indirect harmful effect on embryo/fetus development when Meprezo was prescribed to pregnant women.
Breastfeeding: It is not known whether Esomeprazole is excreted into breast milk. Meprezo should not be used in breastfeeding.
Interaction with other drugs and other types of interactions
Effect on the other drugs pharmacokinetics
Protease inhibitors
Omeprazole interaction with some protease inhibitors has been demonstrated. Clinical significance and mechanisms determined these interactions are not always known. An increase in gastric pH during the treatment with Omeprazole may alter the protease inhibitors absorption. Other possible interaction mechanisms occur due to CYP2C19 inhibition.
It has been reported that Atazanavir and Nelfinavir level in serum decreased when used together with Omeprazole; thus concomitant use is not recommended. Co-administration of Omeprazole (40 mg once a day) with Atazanavir (300 mg) / Ritonavir (100 mg) to healthy volunteers led to a significant decrease in clinical effect of Atazanavir (decrease by approximately 75% in AUC, Cmax and Cmin) – Atazanavir dose increase to 400 mg did not compensate the effect of Omeprazole on Atazanavir exposure. Co-administration of Omeprazole (20 mg once a day) with Atazanavir (400 mg) / Ritonavir (100 mg) to healthy volunteers led to a decrease in Atazanavir exposure by about 30% compared to the effect observed with Atazanavir (300 mg) / Ritonavir (100 mg) once a day without intake of Omeprazole. Co-administration of Omeprazole (40 mg once a day) reduces AUC, Cmax and Cmin of Nelfinavir by 36–39% and an average AUC, Cmax and Cmin of the pharmacologically active metabolite M8 by 75–92%. Due to similar pharmacodynamic effects and pharmacokinetic properties of Omeprazole and Esomeprazole, concomitant administration of Esomeprazole and Atazanavir is not recommended; concomitant administration of Esomeprazole and Nelfinavir is contraindicated. Elevated serum level (80-100%) has been recorded during the treatment with Saquinavir (in concomitant use with Ritonavir) and Omeprazole (40 mg once a day). Treatment with Omeprazole (20 mg once a day) has no effect on Darunavir exposure (in concomitant use with Ritonavir) and Amprenavir (in concomitant use with Ritonavir). Treatment with Esomeprazole (20 mg once a day) has no effect on Amprenavir exposure (with and without concomitant use of Ritonavir). Treatment with Omeprazole (40 mg once a day) has no effect on Lopinavir exposure (in concomitant use with Ritonavir).
Methotrexate
An increase in Methotrexate level has been reported in some patients when combined with PPIs. When prescribing high doses of Methotrexate, it is necessary to consider the possibility of discontinuing Esomeprazole therapy.
Concomitant use of Tacrolimus with Esomeprazole results in serum Tacrolimus level increase. It is necessary to carry out close monitoring of Tacrolimus concentration, as well as renal function (creatinine clearance) and if necessary, adjust the dosage of Tacrolimus.
PH dependent absorption drugs
Suppression of gastric acid secretion during the treatment with Esomeprazole and other PPIs may decrease or increase the absorption rate of the drugs with pH-dependent absorption. As with other drugs that decrease stomach acidity during the treatment with Esomeprazole, the absorption rate of some drugs like ketoconazole, itraconazole and erlotinib may decrease, digoxin absorption may also increase. Concomitant therapy with Omeprazole (20 mg once a day) and Digoxin in healthy volunteers increased Digoxin bioavailability by 10% (up to 30% in two out of ten volunteers). Digoxin toxicity has been rarely reported. However, caution should be exercised when prescribing Esomeprazole at high doses in elderly patients. It is necessary to carry out close therapeutic monitoring of Digoxin.
reactions in patients during 3-days period of i/v treatment with Esomeprazole.
Diazepam
Concomitant oral administration of Esomeprazole 30 mg reduced clearance of diazepam CYP2C19 substrate by 45%.
Phenytoin
Concomitant oral administration of Esomeprazole 40 mg and Phenytoin resulted in plasma Phenytoin level increased by 13% in patients with epilepsy. It is recommended to control Phenytoin plasma concentration, when combined with Esomeprazole or discontinue the therapy.
Voriconazole
Omeprazole (40 mg once a day) increased Cmax and AUCT of Voriconazole (CYP2C19 substrate) by 15% and 41%, respectively.
Cilostazol
A cross-sectional study of Omeprazole 40 mg in healthy volunteers, demonstrated Cilostazol Cmax and AUC increased by 18% and 26%, respectively, as well as one of its active metabolites by 29% and 69%, respectively.
Cisapride
Concomitant oral administration of Esomeprazole 40 mg and Cisapride led to an increase in the area under the plasma concentration-time curve (AUC) by 32% and the half-life prolongation (t1/2) by 31%, but no significant increase in Cisapride maximum plasma concentration was detected. Slight prolongation of QTc interval observed after Cisapride administration did not increase in case of combined use of Cisapride with Esomeprazole.
Warfarin
Concomitant oral administration of Esomeprazole 40 mg in patients used Warfarin as a part of a clinical trial shown that coagulation time remained within the acceptable range. However in the post-marketing period several individual cases of a clinically significant increase in INR were observed when Esomeprazole was taken orally in combined therapy. Close monitoring is recommended at the beginning and at the end of Esomeprazole co-therapy with Warfarin or other coumarin derivatives.
Clopidogrel
The results of studies performed in healthy volunteers have shown pharmacokinetic and pharmacodynamic interactions between Clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and Esomeprazole (40 mg once a day). Clopidogrel active metabolite exposure decreased on average by 40% and maximum inhibition of platelet aggregation (ADP induced) on average decreased by 14 %.
In a study performed in healthy volunteers with the combined use of Clopidogrel with a combination of a fixed dose of Esomeprazole 20 mg + ASA 81 mg compared with the use of Clopidogrel alone, the effect of Clopidogrel active metabolite decreased by almost 40%. However, maximum inhibition of platelet aggregation (ADP induced) in these patients remained the same for Clopidogrel and Clopidogrel + combination (Esomeprazole + ASA).
Drugs that do not demonstrate clinically significant interactions
Amoxicillin or Quinidine
Esomeprazole has no clinically significant effect on Amoxicillin or Quinidine pharmacokinetics.
Naproxen or Rofecoxib
Studies evaluated concomitant administration of Esomeprazole and Naproxen or Rofecoxib have not revealed any clinically significant pharmacokinetic interactions.
Other drugs effect on pharmacokinetics of Esomeprazole
Esomeprazole is metabolized by CYP2C19 and CYP3A4. Concomitant oral administration of Esomeprazole and CYP3A4 inhibitor, Clarithromycin (500 mg BID) resulted in a doubled exposure (AUC) of Esomeprazole. Concomitant administration of Esomeprazole and a combined inhibitor of CYP2C19 and CYP ZA4 can increase the exposure of Esomeprazole by more than twice. CYP2C19 and a CYP3A4 inhibitor Voriconazole increased Omeprazole AUCT by 280%. In such cases Esomeprazole dose adjustment is usually not required. However, dose adjustment is required in patients with severe liver failure and in prolonged treatment period.
Drugs that induce CYP2C19 or CYP3A4 or both enzymes (for example, Rifampicin and St. John's wort) can lead to Esomeprazole serum concentration decreased by its metabolism increased.
Overdose
Data on intentional overdose is limited. Gastrointestinal tract conditions and weakness were demonstrated in 280 mg oral dose intake. Esomeprazole single oral dose of 80 mg and intravenous administration of Esomeprazole 308 mg within 24 hours period were uncomplicated. The specific antidote is not known. Esomeprazole is extensively bound to plasma proteins and is therefore poorly excreted in dialysis. As in any case of overdose, symptomatic treatment is necessary and general supportive measures should be taken.
Drug form
Lyophilized powder for intravenous solution preparation, 40 mg in a class I clear glass vial corked with a bromobutyl (BIR) rubber stopper and rolled in a combined aluminum “flip-off” cap together with a plastic cap.
1 vial with a leaflet placed into a cardboard box.
Storage conditions
Store in a dark place at a temperature not above 25°C
Keep out of reach of children!
The prepared solution is stable for 12 hours at a temperature of not higher than 25°C.
Shelf life
3 years from the production date.
Not to be used after the expiration date.
Prescription Status
On prescription
Manufacturer Information
Foreign production and trade unitary enterprise “Reb-Pharma”, 223216, Republic of Belarus, Minsk region, Chervensky district, Smilovichi, Sadovaya Str., 1, tel./fax: (+375) 17 240 26 35,
Comment type is not specified in the component properties.