Nexium

Esomeprazole.

Each 40 mg vial contains esomeprazole sodium 42.5 mg, equivalent to esomeprazole 40 mg.
Excipients/Inactive Ingredients: Disodium edetate, Sodium hydroxide.

Pharmacotherapeutic Group: Proton pump inhibitor. 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 five 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.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
The effect is similar irrespective of whether esomeprazole is administered orally or intravenously.
During intravenous administration of 80 mg esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/hr for 23.5 hours, intragastric pH above 4, and pH above 6 was maintained for a mean time of 21 hours, and 11-13 hours, respectively, over 24 hours in healthy subjects.
Therapeutic effects of acid inhibition: Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks.
In a randomized, double blind, placebo-controlled clinical study, 764 patients who presented with endoscopically confirmed peptic ulcer bleeding were randomized to receive NEXIUM solution for infusion (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either 80 mg esomeprazole as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for 72 hours. After the initial 72 hour period, all patients received 40 mg oral NEXIUM MUPS for 27 days for acid suppression.
The occurrence of rebleeding within 3 days was 5.9% in the NEXIUM IV treated group compared to 10.3% for the placebo group (p=0.0256). At 7 and 30 days post-treatment, the occurrence of rebleeding in the NEXIUM MUPS treated versus the placebo treated group was 7.2% vs 12.9% (p=0.0096) and 7.7% vs 13.6%, respectively (p=0.0092).
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 some patients 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.
Pharmacokinetics: Distribution: 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.
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.
Following repeated doses of 40 mg administered as intravenous injections, the mean peak plasma concentration is approx. 13.6 micromol/L. The mean peak plasma concentration after corresponding oral doses is approx. 4.6 micromol/L. A smaller increase (of approx 30%) can be seen in the total exposure after intravenous administration.
There is a dose-linear increase in total exposure following intravenous administration of esomeprazole as a 30-minute infusion (40 mg, 80 mg or 120 mg) followed by a continuous infusion (4 mg/h or 8 mg/h) over 23.5 hours.
Special patient populations: Approximately 2.9±1.5% 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%.
Similar differences have been seen for intravenous administration of esomeprazole. These findings have no implications for the posology of NEXIUM.
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.
Similar differences have been observed for intravenous administration of esomeprazole. These findings have no implications for the posology of NEXIUM.
Impaired organ function: 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.
For patients with bleeding ulcers and severe liver impairment, following an initial bolus dose of 80 mg, a maximum continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient.
Toxicology: Preclinical safety data: Preclinical studies reveal no particular hazard for humans, based on conventional studies of single and repeated dose toxicity, embryo-foetal toxicity and mutagenicity. Oral carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects 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.

NEXIUM for injection and infusion is indicated for: Gastric antisecretory treatment when the oral route is not possible, such as: gastroesophageal reflux disease in patients with esophagitis and/or severe symptoms of reflux; healing of gastric ulcers associated with NSAID therapy.
The short-term maintenance of haemostasis and prevention of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.

Adults: Gastric antisecretory treatment when the oral route is not possible: Patients who cannot take oral medication may be treated parenterally with 20-40 mg once daily. Patients with reflux oesophagitis should be treated with 40 mg once daily. Patients treated symptomatically for reflux disease should be treated with 20 mg once daily.
For healing of gastric ulcers associated with NSAID therapy the usual dose is 20 mg once daily.
Usually the IV treatment duration is short and transfer to oral treatment should be made as soon as possible.
Maintenance of haemostasis and prevention of rebleeding of gastric and duodenal ulcers: Following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers, 80 mg should be administered as a bolus infusion over 30 minutes, followed by a continuous intravenous infusion of 8 mg/h given over 3 days (72 hours).
The parenteral treatment period should be followed by acid-suppression therapy with NEXIUM 40 mg tablets once daily for 4 weeks (see prescribing information for NEXIUM MUPS FC tab as follows).
Children and adolescents: NEXIUM IV should not be used in children and adolescents since no data is available.
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: GERD: 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 NEXIUM should not be exceeded (see Pharmacology: Pharmacokinetics under Actions).
Bleeding ulcers: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, following an initial bolus dose of 80 mg NEXIUM for infusion, a continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient (see Pharmacology: Pharmacokinetics under Actions).
Elderly: Dose adjustment is not required in the elderly.
Method of Administration: For preparation of reconstituted solution see Instructions for use and handling under Cautions for Usage.
Injection: 40-mg dose: 5 ml of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes.
20-mg dose: 2.5 ml or half of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of approximately 3 minutes. Any unused solution should be discarded.
Infusion: 40-mg dose: The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
20-mg dose: Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded.
80-mg bolus dose: The reconstituted solution should be given as a continuous intravenous infusion over 30 minutes.
8-mg/h dose: The reconstituted solution should be given as a continuous intravenous infusion over a period of 71.5 hours (calculated rate of infusion of 8 mg/h).

The symptoms described in connection with deliberate NEXIUM overdose (limited experience of doses in excess of 240 mg/day) are transient. Single oral doses of 80 mg esomeprazole and intravenous doses of 308 mg NEXIUM over 24 hrs 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.
Concomitant administration with esomeprazole and drugs such as atazanavir and nelfinavir is not recommended (see Interactions).

In the presence of any alarm symptom (e.g. 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 NEXIUM may alleviate symptoms and delay diagnosis.
Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg 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 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: NEXIUM is not likely to affect the ability to drive or use machines.

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 NEXIUM to pregnant women.
It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore NEXIUM should not be used during breast-feeding.
For esomeprazole limited data on exposed pregnancies are available.

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 e.g. fever, angioedema, anaphylactic reaction/shock.
Metabolism and nutrition disorders: Uncommon: Peripheral oedema. Rare: Hyponatraemia. Very Rare: Hypomagnesaemia; severe hypomagnesaemia may result in hypocalcemia. Hypomagnesaemia may also result in hypokalaemia.
Psychiatric disorders: Uncommon: Insomnia. Rare: Agitation, confusion, depression. Very Rare: Aggression, hallucinations.
Nervous system disorders: Common: Headache. Uncommon: Dizziness, paraesthesia, somnolence. Rare: Taste disturbance.
Eye disorders: Uncommon: 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, encephalopathy in patients with pre-existing liver disease.
Skin and subcutaneous tissue disorders: Common: Administration site reactions*. Uncommon: Dermatitis, pruritus, rash, urticaria. 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 system disorders: Very Rare: Interstitial nephritis.
Reproductive system and breast disorders: Very Rare: Gynaecomastia.
General disorders and administration site conditions: Rare: Malaise, hyperhidrosis.
*Administration site reactions have mainly been observed in a study with high-dose exposure >3 days (72 hours). In the non-clinical program for esomeprazole intravenous formulation there was no evidence of vaso-irritation but a slight tissue inflammatory reaction at the injection site after subcutaneous (paravenous) injection was noted. The non-clinical findings somewhat indicated that the clinical tissue irritation was concentration related.

Effects of esomeprazole on the pharmacokinetics of other drugs: The gastric acid suppression during treatment with esomeprazole and other PPIs, may 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 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 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 concomitant esomeprazole treatment during 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/75 mg 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 CYP2C19. 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_½) 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 (see Contraindications).
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 pharmacokinetic interactions during short-term studies.
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. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC_T 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.
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.

Instructions for use and handling: The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Only clear solution should be used. For single use only.
If the entire reconstituted content of the vial is not required, any unused solution should be discarded in accordance with local requirements.
Injection 40 mg: A solution for injection (8 mg/ml) is prepared by adding 5 mL of 0.9% sodium chloride for intravenous use to the vial with esomeprazole. The reconstituted solution for injection is clear and colourless to very slightly yellow.
Half of the volume should be given if 20 mg should be administered. Any unused solution should be discarded.
Infusion 40 mg: A solution for infusion is prepared by dissolving the content of one vial with esomeprazole 40 mg in up to 100 mL 0.9% sodium chloride for intravenous use.
Infusion 80 mg: A solution for infusion is prepared by dissolving the content of two vials of esomeprazole 40 mg in up to 100 ml of 0.9% sodium chloride for intravenous use. The reconstituted solution for infusion is clear and colourless to very slightly yellow.
Incompatibilities: This medicinal product should not be used with other medicinal products except those mentioned in Instructions for use and handling. The degradation of reconstituted solution is highly pH dependent and the product must therefore only be reconstituted in the specified volume of 0.9% sodium chloride for intravenous use. The reconstituted solution should not be mixed or co-administered in the same infusion set with any other drug.

Store in the original package, in order to protect from light. Vials can however be stored exposed to normal in door light outside the box for up to 24 hrs. Do not store above 30°C.
Shelf-life after reconstitution: Chemical and physical in-use stability has been demonstrated for 12 hours at 30°C. From a microbiological point of view, the product should be used immediately. The reconstituted solution should be used within 12 hours. Do not store above 30°C.

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).

G