Rhea Esomeprazole

Esomeprazole magnesium trihydrate.

Each tablet contains 40 mg esomeprazole (as magnesium trihydrate).

ATC Code: A02B C05.
Pharmacology: Pharmacodynamics: Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.
Site and mechanism of action: Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase - the acid pump and inhibits both basal and stimulated acid secretion.
Effect on gastric acid secretion: After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for 5 days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6 - 7 hours after dosing on day 5.
After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
Following repeated dose administration of 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, the effect on intragastric pH, expressed as change in percentage of time with intragastric pH>4 from baseline, is similar to that observed after esomeprazole 20 mg in adults. In addition, 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, results in a significant reduction in esophageal acid exposure.
Therapeutic effects of acid inhibition: Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks, and in 93% after 8 weeks.
One week treatment with esomeprazole 20 mg b.i.d. and appropriate antibiotics, results in successful eradication of Helicobacter pylori in approximately 90% of patients.
After eradication treatment there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
In a randomised, double blind, placebo controlled clinical study, 764 patients received 80 mg bolus followed by continuous intravenous infusion of Esomeprazole IV for 71.5 hrs followed by continued treatment for 27 days with oral Esomeprazole 40 mg. At 7 and 30 days post-treatment, the occurrence of rebleeding was 7.2% in the treatment group vs. 12.9% in the placebo group and 7.7% vs. 13.6%, respectively.
Other effects related to acid inhibition: During treatment with antisecretory drugs serum gastrin increases in response to the decreased acid secretion. Also chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Literature reports indicate that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurement. Measurements should be repeated if levels have not normalised by this time.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in both children and adults during long term treatment with esomeprazole. The findings are considered to be of no clinical significance.
During long-term treatment with antisecretory drugs gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile.
Comparative Clinical Trials: In a five-way crossover study, the 24 hour intragastric pH profile of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg once daily was evaluated in 24 symptomatic GERD patients. On day 5, intragastric pH was maintained above 4.0 for a mean of 15.3 hours with esomeprazole, 13.3 hours with rabeprazole, 12.9 hours with omeprazole, 12.7 hours with lansoprazole and 11.2 hours with pantoprazole (p≤0.001 for differences between esomeprazole and all other comparators). Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 4.0 for more than 12 hours relative to the other proton pump inhibitors (p <0.05).
Patients requiring continued NSAID therapy: Treatment of NSAID associated upper gastrointestinal symptoms: Esomeprazole was significantly better than placebo in treatment of upper gastrointestinal symptoms in patients using either non-selective or COX-2-selective NSAIDs.
Healing of gastric ulcers associated with NSAID therapy: Esomeprazole was significantly better than ranitidine in healing of gastric ulcers in patients using NSAIDs, including COX-2-selective NSAIDs.
Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: Esomeprazole was significantly better than placebo in prevention of gastric and duodenal ulcers associated with NSAID therapy in patients using NSAIDs, including COX-2-selective NSAIDs.
Patients requiring continued low dose aspirin therapy: Prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk.
Esomeprazole was significantly better than placebo in prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk (prior history of ulcer disease, age ≥60 years with a history of coronary artery disease or age ≥65 years).
Pharmacokinetics: Absorption and distribution: Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once-daily administration. For 20 mg esomeprazole the corresponding values are 50% and 68%, respectively. The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% plasma protein bound.
Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
Metabolism and Excretion: Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.
The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Special patient populations: Approximately 3% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%.
These findings have no implications for the dosage of Esomeprazole.
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Following a single dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the dosage of Esomeprazole.
The metabolism of esomeprazole in patients with mild to moderate liver impairment may be impaired. The metabolic rate is decreased in patients with severe liver impairment resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe hepatic impairment. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.
No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Following repeated dose administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (t_max) in 12 to 18 year-olds was similar to that in adults for both esomeprazole doses.
Following repeated dose administration of 10 mg and 20 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (t_max) for the 10 mg dose was similar across the 1 to 11 years-olds and similar to the total exposure seen with the 20 mg dose in 12 to 18 year-olds and adults. The 20 mg dose resulted in higher exposure in 6 to 11 year-olds compared to 12 to 18 year-olds and adults.
Repeated dose administration of 5 mg esomeprazole resulted in insufficient exposure in 1 to 5 year-olds.
Following repeated dose administration of 1.0 mg/kg esomeprazole in 1 to 11 month old infants, the exposure (AUC) was slightly higher than that observed after 0.5 mg/kg esomeprazole in < 1 month old infants, but similar to that observed after 10 mg in 1 to 11 year-olds, and 20 mg in 12 to 18 year-olds as well as adults.
Toxicology: Preclinical safety data: Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.
There was no unexpected toxicity and/or other effects following esomeprazole treatment of rats or dogs from the neonatal period, during suckling and beyond weaning, compared to those previously observed in adult animals. Neither were there any findings indicating that neonatal/juvenile animals are more susceptible to proliferative changes in the gastric mucosa following esomeprazole treatment. Thus, there were no findings in these juvenile toxicity studies that indicate any specific risk in the pediatric population.

Esomeprazole tablets are indicated for: Gastroesophageal Reflux Disease (GERD): treatment of erosive reflux esophagitis.
Long-term management of patients with healed esophagitis to prevent relapse.
Symptomatic treatment of gastroesophageal reflux disease (GERD).
Patients requiring continued non-steroidal anti-inflammatory (NSAID) therapy: treatment of upper gastrointestinal symptoms associated with non-steroidal anti-inflammatory drug (NSAID) therapy.
Healing of gastric ulcers associated with non-steroidal anti-inflammatory drug (NSAID) therapy, including COX-2 selective NSAIDs.
Prevention of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory drug (NSAID) therapy, including COX-2 selective NSAIDs, in patients at risk.
Patients requiring continued low dose aspirin (75-325 mg) therapy: prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy, in patients at risk.
Following treatment with Esomeprazole IV: Maintenance of hemostasis and prevention of rebleeding of gastric or duodenal ulcers.
In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and: healing of Helicobacter pylori associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.
Pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion.

The tablets should be swallowed whole with liquid. They should not be chewed or crushed.
The tablets can also be also dispersed in half a glass of non-carbonated water. No other liquids should be used. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.
For patients who cannot swallow, the tablet contents can be dispersed in non-carbonated water and administered through a gastric tube.
Adults: Gastroesophageal Reflux Disease (GERD): treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks.
An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.
Long-term management of patients with healed esophagitis to prevent relapse: 20 mg once daily.
Symptomatic treatment of GERD: 20 mg once daily in patients without esophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on demand regimen taking 20 mg once daily, when needed. In NSAID treated risk patients subsequent symptom control using on demand treatment is not recommended.
Patients requiring continued non-steroidal anti-inflammatory (NSAID) therapy: treatment of upper gastrointestinal symptoms associated with NSAID therapy: 20 mg once daily in patients requiring NSAID therapy. If symptom control has not been achieved after 4 weeks, the patient should be further investigated.
Healing of gastric ulcers associated with NSAID therapy: 20 mg or 40 mg once daily for 4 to 8 weeks.
Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: 20 mg or 40 mg once daily.
Patients requiring continued low dose aspirin therapy: prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk: 20 mg or 40 mg once daily.
Maintenance of hemostasis and prevention of rebleeding of gastric or duodenal ulcers following treatment with Esomeprazole IV: 40 mg once daily for 4 weeks. The oral treatment period should be preceded by acid-suppression therapy with Esomeprazole IV 80 mg administered as bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/hr given over 3 days (refer to an Esomperazole IV prescribing information).
In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and: healing of Helicobacter pylori associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers: 20 mg Esomeprazole with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.
Pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion: The recommended initial dosage is Esomeprazole 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. Doses up to 120 mg twice daily have been administered.
Children 12 - 18 years: Gastroesophageal Reflux Disease (GERD): treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks.
An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.
Long-term management of patients with healed esophagitis to prevent relapse: 20 mg once daily.
Symptomatic treatment of gastroesophageal reflux disease (GERD): 20 mg once daily in patients without esophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily under medical supervision.
Treatment of duodenal ulcer caused by H. Pylori: When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents.
The treatment should be supervised by a specialist.
The dosage recommendation for esomeprazole is the following: 20 mg twice daily for one week.
Children 1 - 11 years: Gastroesophageal Reflux Disease (GERD): treatment of erosive reflux esophagitis: Weight <20 kg: 10 mg once daily for 8 weeks. Weight ≥20 kg: 10 mg or 20 mg once daily for 8 weeks.
Long-term management of patients with healed esophagitis to prevent relapse: 10 mg once daily.
Symptomatic treatment of gastroesophageal reflux disease (GERD): 10 mg once daily for up to 8 weeks.
Doses over 1 mg/kg/day have not been studied.
Children 0 - 1 year: Gastroesophageal Reflux Disease (GERD): Treatment of gastroesophageal reflux disease (GERD) diagnostically confirmed through pH probe or endoscopy.
1 - 11 months: Weight 3 kg to 5 kg: 2.5 mg once daily for up to 6 weeks.
Weight > 5 kg to 7.5 kg: 5 mg once daily for up to 6 weeks.
Weight >7.5 kg to 12 kg: 10 mg once daily for up to 6 weeks.
Doses over 1.33 mg/kg/day have not been studied.
0 - 1 month: Weight > 2.5 kg: 2.5 mg once daily for up to 4 weeks.
Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution. (See Pharmacology: Pharmacokinetics under Actions.)
Impaired hepatic function: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum daily dose of 20 mg Esomeprazole should not be exceeded. (See Pharmacology: Pharmacokinetics under Actions.)
Elderly: Dose adjustment is not required in the elderly.

The symptoms described in connection with deliberate Esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg esomeprazole were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the formulation.

In the presence of any alarm symptom (eg, significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with Esomeprazole may alleviate symptoms and delay diagnosis.
Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing Esomeprazole for on demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered. (See Interactions.)
When prescribing Esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4 such as cisapride.
Concomitant administration with esomeprazole and drugs such as atazanavir and nelfinavir is not recommended (see Interactions).
Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75mg daily maintenance dose) and esomeprazole (40 mg p.o. 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%. Based on these data, concomitant use of esomeprazole and clopidogrel should be avoided. See also Interactions.
Some published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with a small increased risk for osteoporosis related fractures. However, in other similar observational studies no such increased risk was found.
In AstraZeneca's randomized, double-blind and controlled clinical studies on omeprazole and esomeprazole (including two open long-term studies of up to more than 12 years) there are no indications that PPIs are associated with osteoporotic fractures.
Although a causal relationship between omeprazole/esomeprazole and osteoporotic fractures has not been established, patients at risk for developing osteoporosis or osteoporotic fractures are advised to have appropriate clinical monitoring in accordance with current clinical guidelines for these conditions.
Effects on ability to drive and use machines: Esomeprazole is not likely to affect the ability to drive or use machines.

For Esomeprazole limited clinical data on exposed pregnancies are available. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.
It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore Esomeprazole should not be used during breast-feeding.

The following definitions of frequencies are used: Common ≥1/100; Uncommon ≥1/1000 and <1/100; Rare ≥ 1/10000 and <1/1000; Very rare <1/10000.
The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole and/or from post-marketing use. None was found to be dose-related.
Blood and lymphatic system disorders: Rare: Leukopenia, thrombocytopenia.
Very rare: Agranulocytosis, pancytopenia.
Immune system disorders: Rare: Hypersensitivity reactions eg, angioedema and anaphylactic reaction/shock.
Metabolism and nutrition disorders: Uncommon: Peripheral oedema.
Rare: Hyponatraemia.
Very Rare: Hypomagnesaemia; severe hypomagnesaemia may result in hypocalcaemia.
Hypomagnesaemia may also result in hypokalaemia.
Psychiatric disorders: Uncommon: Insomnia.
Rare: Agitation, confusion, depression.
Very rare: Aggression, hallucination.
Nervous system disorders: Common: Headache.
Uncommon: Dizziness, paraesthesia, somnolence.
Rare: Taste disturbance.
Eye disorders: Rare: Blurred vision.
Ear and labyrinth disorders: Uncommon: Vertigo.
Respiratory, thoracic and mediastinal disorders: Rare: Bronchospasm.
Gastrointestinal disorders: Common: Abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation.
Uncommon: Dry mouth.
Rare: Stomatitis, gastrointestinal candidiasis.
Very rare: Microscopic colitis.
Hepatobiliary disorders: Uncommon: Increased liver enzymes.
Rare: Hepatitis with or without jaundice.
Very rare: Hepatic failure, hepatic encephalopathy.
Skin and subcutaneous tissue disorders: Uncommon: Dermatitis, pruritus, urticaria, rash.
Rare: Alopecia, photosensitivity.
Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).
Musculoskeletal, connective tissue and bone disorders: Rare: Arthralgia, myalgia.
Very rare: Muscular weakness.
Renal and urinary disorders: Very rare: Interstitial nephritis.
Reproductive system and breast disorders: Very rare: Gynaecomastia.
General disorders and administration site conditions: Rare: Malaise, hyperhidrosis.

Effects of esomeprazole on the pharmacokinetics of other drugs: The gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of drugs with a gastric pH dependent absorption. Like with other drugs that decrease the intragastric acidity, the absorption of drugs, such as ketoconazole, itraconazole and erlotinib can decrease while the absorption of drugs such as 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).
Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance. Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients; dose adjustment was not required in this study. Concomitant administration of 40 mg esomeprazole to warfarin-treated patients showed that, despite a slight elevation in the trough plasma concentration of the less potent R‑isomer of warfarin, the coagulation times were within the accepted range. However, from post marketed use cases of elevated INR of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when initiating and ending treatment with warfarin or other coumarine derivatives.
Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75mg daily maintenance dose) and esomeprazole (40 mg p.o. 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%.
It is, however, uncertain to what extent this interaction is clinically important. One prospective, randomized (but incomplete) study (in over 3760 patients comparing placebo with omeprazole 20 mg in patients treated with clopidogrel and ASA) and non-randomized, post-hoc analyses of data from large, prospective, randomized clinical outcome studies (in over 47000 patients) did not show any evidence of an increased risk for adverse cardiovascular outcome when clopidogrel and PPIs, including esomeprazole, were given concomitantly.
Results from a number of observational studies are inconsistent with regard to increased risk or no increased risk for CV thromboembolic events when clopidogrel is given together with a PPI.
When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups, likely due to the concomitant administration of low dose ASA.
Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C_max and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
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 (t_1/2) 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 (see Precautions).
Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus.
When given together with proton pump inhibitors, 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.
Omeprazole has been reported to interact with some antiretroviral drugs. 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 antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. For other antiretroviral drugs, such as saquinavir, increased serum levels have been reported. There are also some antiretroviral drugs for which unchanged serum levels have been reported when given with omeprazole. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and antiretroviral drugs such as atazanavir and nelfinavir is not recommended.
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interaction.
Effects of other drugs on the pharmacokinetics of esomeprazole: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg 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, such as voriconazole, may result in more than doubling of the esomeprazole exposure. However, dose adjustment of esomeprazole is not required in either of these situations.
Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Store at a temperature not exceeding 30°C.
Store in the original package (blister).

Antacids, Antireflux Agents & Antiulcerants

A02BC05 - esomeprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

Rx