Nexium/Nexium MUPS

Nexium/Nexium MUPS

esomeprazole

Manufacturer:

AstraZeneca

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Esomeprazole.
Description
Nexium: Each vial contains esomeprazole 40 mg (as sodium salt).
Each vial contains 1 <mmol sodium.
Nexium MUPS: Each tablet contains: 20 mg or 40 mg esomeprazole (as magnesium trihydrate).
Excipients: Nexium 20 mg: Sucrose 28 mg. Nexium 40 mg: Sucrose 30 mg.
Nexium MUPS is a proton pump inhibitor. The active ingredient in Nexium MUPS is esomeprazole magnesium trihydrate, a substituted benzimidazole. Esomeprazole is the S-isomer of omeprazole. It is optically stable in vivo, with negligible conversion to the R-isomer. The chemical name is di-(S)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl] -1H- benzimidazole magnesium salt trihydrate.
Molecular formula: C34H36N6O6S2Mg·3H2O.
Molecular weight: 767.2 (trihydrate).
Excipients/Inactive Ingredients: Nexium: Disodium edetate, Sodium hydroxide (for pH adjustment).
Nexium MUPS: Glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide (E 172) (Tablet 20 mg, reddish-brown CI 77491, yellow, CI 77492) (Tablet 40 mg, reddish-brown CI 77491), magnesium stearate, methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30 percent, cellulose microcrystalline, synthetic paraffin, macrogols, polysorbate 80, crospovidone, sodium stearyl fumarate, sugar spheres (sucrose and maize starch), talc, titanium dioxide (E 171), triethyl citrate.
Action
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.
Effects on gastric acid secretion: Nexium: 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 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 80 mg 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.
Nexium MUPS: 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 five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6 - 7 hours after dosing on day five.
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. 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.
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 of oral treatment.
In a randomized, double blind, placebo-controlled clinical study, patients with endoscopically confirmed peptic ulcer bleeding characterised as Forrest Ia, Ib, IIa or IIb (9%, 43%, 38% and 10 % respectively) were randomized to receive Nexium solution for infusion (n=375) or placebo (n=389). Following endoscopic haemostasis, 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 open-label 40 mg oral Nexium for 27 days for acid suppression. The occurrence of rebleeding within 3 days was 5.9% in the Nexium treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleeding in the Nexium treated versus the placebo treated group 7.7% vs 13.6%.
Nexium MUPS: 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 for one week there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
Other effects related to acid inhibition: During treatment with antisecretory medicinal products 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. 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 orally administered esomeprazole. The findings are considered to be of no clinical significance.
During long-term oral 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 hospitalised patients, possibly also Clostridium difficile.
Nexium MUPS: In two studies with ranitidine as an active comparator, Nexium showed better effect in healing of gastric ulcers in patients using NSAIDs, including COX-2 selective NSAIDs.
In two studies with placebo as comparator, Nexium showed better effect in the prevention of gastric and duodenal ulcers in patients using NSAIDs (aged >60 and/or with previous ulcer), including COX-2 selective NSAIDs.
Pharmacokinetics: Nexium: 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. 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 sulphone metabolite.
Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.
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 compared to oral 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.
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 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 40 mg 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.
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Following a single oral dose of 40 mg 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.
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 20 mg 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 80 mg, 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.
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.
Nexium MUPS: 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 as follows 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 pharmacokinetics of esomeprazole has been studied in doses up to 40 mg b.i.d. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a more than dose proportional increase in AUC 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 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%. These findings have no implications for the posology 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 posology of esomeprazole.
Impaired organ function: 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 area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe dysfunction. 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.
Adolescents 12-18 years: Following repeated dose administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (tmax) in 12 to 18-year-olds was similar to that in adults for both esomeprazole doses.
Toxicology: Preclinical Safety Data: Nexium: 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. 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. See Adverse Reactions.
Indications/Uses
Nexium: 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 associate with NSAID therapy.
prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.
Prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.
Nexium MUPS: Nexium MUPS 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).
In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori: healing of Helicobacter pylori associated duodenal ulcer and; prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.
Patients requiring continued NSAID therapy: healing of gastric ulcers associated with NSAID therapy; prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.
Prolonged treatment after i.v. induced prevention of rebleeding of peptic ulcers.
Treatment of Zollinger Ellison Syndrome.
Dosage/Direction for Use
Nexium: 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. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be treated with 20 mg once daily.
Usually the intravenous treatment duration is short and transfer to oral treatment should be made as soon as possible. Treatment with Nexium IV can be given for up to 10 days as part of a full treatment period for the specified indications.
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 oral acid suppression therapy.
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 at least 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).
Children and adolescents: Nexium should not be used in children 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.
Nexium MUPS: The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed. For patients who have difficulty in swallowing the tablets can also be dispersed in half a glass of non-carbonated water. No other liquids should be used as the enteric coating may be dissolved. Stir until the tablets disintegrate and drink the liquid with 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 tablets can be dispersed in non-carbonated water and administered through a gastric tube. It is important that the appropriateness of the selected syringe and tube is carefully tested. For preparation and administration instructions please see "Instructions for Use and Handling" under Cautions for Usage.
Adults and adolescents from the age of 12 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. In adults, an on demand regimen taking 20mg once daily, when needed, can be used. In NSAID treated patients at risk of developing gastric cancer and duodenal ulcers, subsequent symptom treatment using an on demand regimen is not recommended.
Adults: 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 Nexium MUPS with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.
Patients requiring continued NSAID therapy: healing of gastric ulcers associated with NSAID therapy: The usual dose is 20 mg once daily.
The treatment duration is 4-8 weeks.
prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: 20 mg once daily.
Prolonged treatment after i.v. induced prevention of rebleeding of peptic ulcers: 40 mg once daily for 4 weeks after i.v. induced prevention of rebleeding of peptic ulcers.
Treatment of Zollinger Ellison Syndrome: The recommended initial dosage is Nexium MUPS 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. Based on the clinical data available, the majority of patients can be controlled on doses between 80 to 160 mg esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice daily.
Children below the age of 12 years: Nexium MUPS should not be used in children younger than 12 years 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: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg Nexium MUPS should not be exceeded (see Pharmacology: "Pharmacokinetics" under Actions).
Elderly: Dose adjustment is not required in the elderly.
Overdosage
There is very limited experience to date with deliberate overdose. The symptoms described in connection with an oral dose of 280 mg were gastrointestinal symptoms and weakness. Single oral doses of 80 mg esomeprazole and intravenous doses of 308 mg 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 utilised.
Contraindications
Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the formulation.
Esomeprazole should not be used concomitantly with nelfinavir (See "Interactions").
Special Precautions
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrentvomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present,malignancy should be excluded, as treatment with Nexium may alleviate symptoms and delaydiagnosis.Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinalinfections such as Salmonella and Campylobacter (see Pharmacology: "Pharmacodynamics" under Actions).Co-administration of esomeprazole with atazanavir is not recommended (see "Interactions"). Ifthe combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinicalmonitoring is recommended in combination with an increase in the dose of atazanavir to 400mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded.
Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole,the potential for interactions with drugs metabolised through CYP2C19 should be considered.An interaction is observed between clopidogrel and esomeprazole (see "Interactions"). Theclinical relevance of this interaction is uncertain. As a precaution, concomitant use ofesomeprazole and clopidogrel should be discouraged.
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 esomeprazole. 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 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 recognised 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.
Absorption of Vitamin B12: Esomeprazole, as all acid-blocking medicines, may reduce the absorption of Vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced Vitamin B12 absorption on long-term therapy.
Interference with laboratory tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be stopped for at least 5 days before CgA measurements (see Pharmacology: Pharmacodynamics under Actions). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of PPI treatment.
Nexium: Regular Surveillance: Patients on proton pump inhibit treatment (particularly those treated for long term) should be kept under regular surveillance.
Nexium MUPS: 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.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Effects on Ability to Drive and Use Machines: No effects have been observed.
Use In Pregnancy & Lactation
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/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 breastfeeding.
Nexium MUPS: With the racemic mixture omeprazole, data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effects.
Adverse Reactions
The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole and post-marketing. None was found to be dose-related. The reactions are classified according to frequency (common >1/100, <1/10; uncommon >1/1000, <1/100; rare: >1/10000, <1/1000; very rare: <1/10000; not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: Rare: Leukopenia, thrombocytopenia. Very rare: Agranulocytosis, pancytopenia.
Immune system disorders: Rare: Hypersensitivity reactions e.g. fever, 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, 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, constipation, diarrhoea, flatulence, nausea/vomiting. 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: Uncommon: Dermatitis, pruritus, rash, urticaria. Rare: Alopecia, photosensitivity. Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN). Not known: Subacute cutaneous lupus erythematosus (SCLE).
Musculoskeletal, connective tissue and bone disorders: Uncommon: Fracture of the hip, wrist or spine. 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, increased sweating.
Other possible side effects include Clostridium difficile diarrhoea and Vitamin B12 deficiency (with unknown frequency).
Nexium: *Administration site reactions have mainly been observed in a study with high-dose exposure over 3 days (72 hours). See Pharmacology: Toxicology: "Preclinical Safety Data" under Actions.
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.
Drug Interactions
Interaction studies have only been performed in adults.
Effects of esomeprazole on the pharmacokinetics of other drugs: Medicinal products with pH dependent absorption: Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease the intragastric acidity, the absorption of medicinal products, such as ketoconazole, itraconazole and erlotinib and 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). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced.
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. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg qd) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg qd without omeprazole 20 mg qd. Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, Cmax and Cmin by 36-39 % and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75-92%. For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg qd). Treatment with omeprazole 20 mg qd had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg qd had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg qd had no effect on the exposure of lopinavir (with concomitant ritonavir). 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.
Drugs metabolised by CYP2C19: Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with drugs metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these drugs may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on demand therapy. Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of 40 mg esomeprazole 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. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUCτ by 15% and 41%, respectively.
Concomitant administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.
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 (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 (see Precautions).
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) 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 aggression by an average of 14%.
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.
Inconsistent data on the clinical implications of a PK/PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution concomitant use of clopidogrel should be discouraged.
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 Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
Nexium: No in vivo interaction studies have been performed with the high dose intravenous regimen (80mg+8mg/h). The effect of esomeprazole on drugs 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.
Nexium MUPS: Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.
Unknown Mechanism: 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.
Effects 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 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCτ 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.
Caution For Usage
Instructions for Use and Handling: Administration through gastric tube: 1. Put the tablet into an appropriate syringe and fill the syringe with approximately 25 ml of water and approximately 5 ml air. For some tubes, dispersion in 50 ml water is needed to prevent the pellets from clogging the tube.
2. Immediately shake the syringe for approximately 2 minutes to disperse the tablet.
3. Hold the syringe with the tip up and check that the tip has not clogged.
4. Attach the syringe to the tube whilst maintaining the above position.
5. Shake the syringe and position it with the tip pointing down. Immediately inject 5-10 ml into the tube. Invert the syringe after injection and shake (the syringe must be held with the tip pointing up to avoid clogging of the tip).
6. Turn the syringe with the tip down and immediately inject another 5-10 ml into the tube. Repeat this procedure until the syringe is empty.
7. Fill the syringe with 25 ml of water and 5 ml of air and repeat step 5 if necessary to wash down any sediment left in the syringe. For some tubes, 50 ml water is needed.
Incompatibilities: This medicinal product should not be used with other medicinal products except those mentioned previously.
Storage
Nexium: 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 hours. Do not store above 30°C.
Nexium MUPS: Store in the original package in order to protect from moisture. Do not store above 30°C
ATC Classification
A02BC05 - esomeprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).
Presentation/Packing
Nexium powd for soln for inj 40 mg (white to off-white porous cake or powder in vial) x 1's. Nexium MUPS DR-FC tab 20 mg (light pink, oblong, biconvex, engraved 20 mg on one side and
Click on icon to see table/diagram/image
on the other side) x 14's. 40 mg (pink, oblong, biconvex, engraved 40 mg on one side and
Click on icon to see table/diagram/image
on the other side) x 14's.
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