Vaxcel Esomeprazole

Esomeprazole sodium.

Each vial contains: Esomeprazole Sodium equivalent to Esomeprazole 40mg.

Pharmacotherapeutic group: Drugs for acid-related disorders, proton pump inhibitor. ATC Code: A02B C05.
Pharmacology: 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. 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.
Effect on Gastric Acid Secretion: After 5 days of oral dosing with 20mg and 40mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours respectively, over 24 hours in symptomatic gastroesophageal reflux disease (GERD) patients. The effect is similar irrespective of whether esomeprazole is administered orally or intravenously. Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown after oral administration of esomeprazole. During intravenous administration of 80mg esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/h 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 40mg occurs in approximately 78% of patients after 4 weeks, and in 93% after 8 weeks of oral treatment.
Other Effects Related To Acid Inhibition: During treatment with antisecretory drugs serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range. 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 oral treatment with antisecretory medicinal products, 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.
Pharmacokinetics: Distribution: The apparent volume of distribution at steady state in healthy subjects is approximately 0.22L/kg body weight. Esomeprazole is 97% plasma protein bound.
Metabolism and Excretion: Biotransformation: 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 sulfone, the main metabolite in plasma.
Elimination: The parameters as follows reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers. Total plasma clearance is about 17L/h after a single dose and about 9L/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. 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 medicinal product is found in urine.
Linearity/Non-Linearity: Total exposure (AUC) 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 inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite. Following repeated doses of 40mg 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 total exposure after intravenous administration compared to oral administration. There is a dose-linear increase in total exposure following intravenous administration of esomeprazole as a 30-minute infusion (40mg, 80mg or 120mg) followed by a continuous infusion (4mg/h or 8mg/h) over 23.5 hours.
Special Patient Populations: Poor metabolisers: Approximately 2.9 ± 1.5% of the population lacks a functional CYP2C19 enzyme and is called poor metabolisers. In these individuals, the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40mg oral esomeprazole, the mean total exposure was approximately 100% higher in poor metabolisers than in subjects with 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 esomeprazole.
Gender: Following a single oral dose of 40mg esomeprazole the mean total exposure 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 esomeprazole.
Hepatic Impairment: The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the total exposure of esomeprazole. Therefore, a maximum dose of 20mg should not be exceeded in GERD patients with severe dysfunction. For patients with bleeding ulcers and severe liver impairment, following an initial bolus dose of 80mg, a maximum continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.
Renal Impairment: 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.
Older People: The metabolism of esomeprazole is not significantly changed in elderly subjects (71- 80 years of age).

Vaxcel Esomeprazole 40mg for injection and infusion is indicated for: a) Gastric antisecretory treatment when the oral route is not possible, such as: gastroesophageal reflux disease (GERD) in patients with esophagitis and/or severe symptoms of reflux; healing of gastric ulcers associated with NSAID therapy; prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.
b) Prevention of rebleeding 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 20-40mg once daily. Patients with reflux esophagitis should be treated with 40mg once daily. Patients treated symptomatically for reflux disease should be treated with 20mg once daily. For healing of gastric ulcers associated with NSAID therapy the usual dose is 20mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be treated with 20mg once daily. Usually the intravenous treatment duration is short and transfer to oral treatment should be made as soon as possible.
Prevention of Rebleeding of Gastric and Duodenal Ulcers: Following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers, 80mg should be administered as a bolus infusion over 30 minutes, followed by a continuous intravenous infusion of 8mg/h given over 3 days (72 hours). The parenteral treatment period should be followed by oral acid suppression therapy.
Method of Administration: For preparation of reconstituted solution, see Instruction for Use and Handling as follows.
Injection: 40mg dose: 5ml of the reconstituted solution (8mg/ml) should be given as an intravenous injection over a period of at least 3 minutes.
20mg dose: 2.5ml or half of the reconstituted solution (8mg/ml) should be given as an intravenous injection over a period of at least 3 minutes.
Infusion: 40mg dose: The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
20mg dose: Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
80mg bolus dose: The reconstituted solution should be given as a continuous intravenous infusion over 30 minutes.
8mg/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 8mg/h).
Special Populations: Patients with 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).
Patients with 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 20mg Vaxcel Esomeprazole 40mg Powder for Injection I.V. 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 80mg Vaxcel Esomeprazole 40mg Powder for Injection for infusion, a continuous intravenous infusion dose of 4mg/h for 71.5 hours may be sufficient (see Pharmacology: Pharmacokinetics under Actions).
Older People: Dose adjustment is not required in the elderly.
Instruction 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. 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. From a microbiological point of view, the product is recommended to be used immediately.
Injection: Injection 40mg: A solution for injection (8mg/ml) is prepared by adding 5 ml of 0.9% sodium chloride for intravenous use to the esomeprazole 40 mg vial. The reconstituted solution for injection is clear and colourless to very slightly yellow. The reconstituted solution should be given as an intravenous injection over a period of at least 3 minutes. Half of the volume should be given if 20mg should be administered. Any unused solution after 24 hours should be discarded.
Infusion: Infusion 40mg: A solution for infusion is prepared by dissolving the content of one vial with esomeprazole 40mg in up to 100ml of 0.9% sodium chloride for intravenous use. Half of the volume should be given if 20mg should be administered. Any unused solution after 24 hours should be discarded.
Infusion 80mg: A solution for infusion is prepared by dissolving the contents of two vials of esomeprazole 40mg in up to 100ml of 0.9% sodium chloride for intravenous use.
The reconstituted solution for infusion is clear and colourless to very slightly yellow. The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
Route of Administration: for intravenous injection & infusion only.

There is very limited experience to date with deliberate overdose. The symptoms described in connection with an oral dose of 280mg were gastrointestinal symptoms and weakness. Single oral doses of 80mg esomeprazole and intravenous doses of 308mg esomeprazole over 24 hours 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 utilized.

Hypersensitivity to any of the ingredient of this product. Esomeprazole should not be used concomitantly with nelfinavir (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 Vaxcel Esomeprazole 40mg Powder for Injection may alleviate symptoms and delay diagnosis.
Gastrointestinal Infections: Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.
Combination with Other Medicines: Co-administration of esomeprazole with atazanavir is not recommended. If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400mg with 100mg of ritonavir; esomeprazole 20mg should not be exceeded.
Interference with Laboratory Tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. If the patient(s) are due to have a test on Chromogranin A level, this product treatment should be stopped for at least 5 days before CgA measurements to avoid this interference. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.
Regular Surveillance: Patients on proton pump inhibitor treatment (particularly those treated for long term) should be kept under regular surveillance.
Subacute Cutaneous Lupus Erythematosus (SCLE): Proton pump inhibitors are associated with very infrequent cases of subacute cutaneous lupus erythematosus (SCLE). If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Vaxcel Esomeprazole 40mg Powder for Injection. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with PPI like Esomeprazole Sodium for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPI with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
Fracture: Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognized risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10-40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of Vitamin D and Calcium.
Clostridium Difficile Diarrhea: Published observational studies suggest that PPI therapy may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Vitamin B12 Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
Effects on Ability To Drive and Use Machines: Esomeprazole is not likely to affect the ability to drive or use machines.

Pregnancy: For esomeprazole limited data on exposed pregnancies are available. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/foetal 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 Vaxcel Esomeprazole 40mg Powder for Injection to pregnant women.
Breast-Feeding: It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore Vaxcel Esomeprazole 40mg Powder for Injection should not be used during breast feeding.

The following adverse medicinal product reactions have been identified or suspected for esomeprazole administered orally or intravenously. (See table.)

Click on icon to see table/diagram/image

Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole (the racemate) intravenous injection, especially at high doses, but no causal relationship has been established.

Effects of esomeprazole on the pharmacokinetics of other medicinal products.
Medicinal products with pH dependent absorption: The decreased intragastric acidity during treatment with esomeprazole might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can decrease during treatment with esomeprazole.
Omeprazole has been reported to interact with some protease inhibitors. 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 protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP 2C19. For atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended.
Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated.
Medicinal products metabolised by CYP2C19: Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these medicinal products may be increased and a dose reduction could be needed.
No in vivo interaction studies have been performed with the high dose intravenous regimen (80 mg+8 mg/h). The effect of esomeprazole on medicinal products metabolised by CYP2C19 may be more pronounced during this regimen, and patients should be monitored closely for adverse effects, during the 3 day intravenous treatment period.
Diazepam: Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.
Phenytoin: Concomitant oral administration of 40 mg esomeprazole and phenytoin resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.
Voriconazole: Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUCt by 15% and 41%, respectively.
Cisapride: Concomitant oral administration of 40 mg esomeprazole and cisapride resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t½) 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.
Warfarin: Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.
Amoxicillin or quinidine: Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
Effects of other medicinal products on the pharmacokinetics of esomeprazole medicinal products which inhibit CYP2C19 and/or CYP3A4: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral 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 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCt 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.
Incompatibilities: This medicinal product should not be used with other medicinal products except those mentioned in Instruction for Use and Handling under Dosage & Administration.

The powder vial should be stored below 30°C. Reconstituted solution can be stored for 24 hours below 25°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).

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