Nexium耐信

Nexium

esomeprazole

Manufacturer:

AstraZeneca

Distributor:

Zuellig
/
Four Star
Full Prescribing Info
Contents
Esomeprazole magnesium.
Description
Nexium also contains the following excipients: Tablet: Glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide [reddish brown (20-mg and 40-mg); yellow (20-mg)] (E172), magnesium stearate, methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30%, microcrystalline cellulose, synthetic paraffin, macrogols, polysorbate 80, crospovidone, sodium stearyl fumarate, sugar spheres (sucrose and maize starch), talc, titanium dioxide (E171) and triethyl citrate.
Granules: Esomeprazole Granules: Glycerol monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30%, polysorbate 80, sugar spheres (sucrose and maize starch), talc and triethyl citrate. Excipient Granules: Anhydrous citric acid (for pH adjustment), crospovidone, glucose, hydroxypropyl cellulose, yellow iron oxide (E172) and xanthan gum.
Action
Pharmacotherapeutic Group: Proton-pump inhibitor. ATC Code: A02BC05.
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 hydrogen-potassium (H+K+)-ATPase, the acid pump, and inhibits both basal and stimulated acid secretion.
Effect on Gastric Acid Secretion: After oral dosing with esomeprazole 20 mg and 40 mg, the onset of effect occurs within 1 hr. After repeated administration with esomeprazole 20 mg once daily for 5 days, mean peak acid output after pentagastrin stimulation is decreased by 90% when measured 6-7 hrs after dosing on day 5.
After 5 days of oral dosing with esomeprazole 20 mg and 40 mg, intragastric pH >4 was maintained for a mean time of 13 hrs and 17 hrs, respectively, over 24 hrs in symptomatic gastroesophageal reflux disease (GERD) patients. The proportion of patients maintaining an intragastric pH >4 for at least 8, 12 and 16 hrs, respectively, were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
Using area under the concentration-time curve (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 4 weeks and in 93% after 8 weeks.
Tablet: One (1) week treatment with esomeprazole 20 mg twice daily and appropriate antibiotics, results in successful eradication of Helicobacter pylori in approximately 90% of patients. After eradication treatment for 1 week, there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
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 hemostasis, patients received either esomeprazole 80 mg as an IV infusion over 30 min followed by a continuous infusion of 8 mg/hr or placebo for 72 hrs. After the initial 72-hr period, all patients received open-label oral Nexium 40 mg 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% versus 13.6%.
Other Effects Related to Acid Inhibition: During treatment with antisecretory drugs serum gastrin increases in response to the decreased acid secretion. Chromogranin A (CgA) also increases due to decreased gastric acidity. 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.
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 Clostridium difficile.
Tablet: In 2 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 2 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.
Granules: Pediatric GERD- 1 to 11 Years of Age: In a multicenter, parallel-group study, 109 pediatric patients with endoscopically proven GERD (1-11 years of age) were treated with Nexium once daily for up to 8 weeks to evaluate safety and tolerability. Dosing by patient weight was as follows: weight <20 kg: once daily treatment with esomeprazole 5 mg or 10 mg; weight ≥20 kg: once daily treatment with esomeprazole 10 mg or 20 mg.
Patients were endoscopically characterized as to the presence or absence of erosive esophagitis. Fifty-three (53) patients had erosive esophagitis at baseline. Of the 45 patients who had follow-up endoscopy, 43 (93.3%) of these patients had their erosive esophagitis healed through 8 weeks.
GERD- 0 to 11 months of age: In a placebo-controlled study (98 patients aged 1 11 months) efficacy and safety in patients with signs and symptoms of GERD were evaluated. Esomeprazole 1 mg/kg once daily was given for 2 weeks (open-label phase) and 80 patients were included for an additional 4 weeks (double-blind, treatment-withdrawal phase). There was no significant difference between esomeprazole and placebo for the primary endpoint time to discontinuation due to symptom worsening.
In a placebo-controlled study (52 patients aged <1 month) efficacy and safety in patients with symptoms of GERD were evaluated. Esomeprazole 0.5 mg/kg once daily was given for a minimum of 10 days. There was no significant difference between esomeprazole and placebo in the primary endpoint, change from baseline of number of occurrences of symptoms of GERD. Results from the paediatric studies further show that 0.5 mg/kg and 1.0 mg/kg esomeprazole in <1 month old and 1-11 month old infants, respectively, reduced the mean percentage of time with intra-oesophageal pH <4.
The safety profile appeared to be similar to that seen in adults.
Pharmacokinetics: Absorption and Distribution: Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hrs after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once-daily administration. For esomeprazole 20 mg, 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 P-450 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 following parameters reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 17 L/hr after a single dose and about 9 L/hr after repeated administration. The plasma elimination half-life (t½) is about 1.3 hrs after repeated once-daily dosing. The pharmacokinetics of esomeprazole has been studied in doses up to 40 mg twice daily. The AUC 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 esomeprazole 40 mg, the mean AUC was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations (Cmax) were increased by about 60%.
These findings have no implications for the dosage of esomeprazole.
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years).
Following a single dose of esomeprazole 40 mg, the mean AUC is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the dosage of esomeprazole.
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 AUC 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.
Pediatric: Adolescents 12-18 years: Following repeated dose administration of esomeprazole 20 mg and 40 mg in adolescents 12-18 years, the total exposure (AUC) and the time to reach maximum plasma drug concentration (tmax) was similar to that in adults for both esomeprazole doses.
Granules: Children 1-11 years: Following repeated-dose administration of esomeprazole 10 mg, the total exposure (AUC) was similar within the age range 1-11 years and the exposure was similar to the exposure seen with the 20-mg dose in adolescents and adults.
Following repeated dose administration of esomeprazole 20 mg, the total exposure (AUC) was higher in 6-11 years compared to the same dose in adolescents and adults.
Indications/Uses
Tablet: Gastroesophageal Reflux Disease (GERD): Treatment of erosive reflux esophagitis; long-term management of patients with healed esophagitis to prevent relapse; symptomatic treatment of GERD.
In Combination with Appropriate Antibacterial Therapeutic Regimens: Eradication of Helicobacter pylori; healing of H. pylori-associated duodenal ulcer; and prevention of relapse of peptic ulcers in patients with H. 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 IV-induced prevention of rebleeding of peptic ulcers.
Treatment of Zollinger Ellison syndrome.
Granules: Nexium oral suspension is primarily indicated for treatment of GERD in children 1-11 years old.
Gastroesophageal Reflux Disease (GERD): Treatment of endoscopically proven erosive reflux esophagitis; symptomatic treatment of GERD.
Nexium oral suspension may also be used by patients having difficulty in swallowing dispersed Nexium gastro-resistant tablets. For indications in patients ≥12 years, reference is made to the Nexium gastro-resistant tablet prescribing information.
Dosage/Direction for Use
Tablet: Adults and Adolescents ≥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 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 20 mg once daily, when needed, can be used. In NSAID-treated patients at risk of developing gastric and duodenal ulcers, subsequent symptom control using an on demand regimen is not recommended.
Adults: In Combination with Appropriate Antibacterial Therapeutic Regimens for the Eradication of H. pylori, Healing of H. pylori-Associated Duodenal Ulcer and Prevention of Relapse of Peptic Ulcers in Patients with H. pylori-Associated Ulcers: 20 mg with amoxicillin 1 g and clarithromycin 500 mg, all twice daily for 7 days.
Patients Requiring Continued NSAID Therapy: Healing of Gastric Ulcers Associated with NSAID Therapy: Usual Dose: 20 mg once daily. Treatment Duration: 4-8 weeks.
Prevention of Gastric and Duodenal Ulcers Associated with NSAID Therapy in Patients at Risk: 20 mg once daily.
Prolonged Treatment After IV-Induced Prevention of Rebleeding of Peptic Ulcers: 40 mg once daily for 4 weeks after IV-induced prevention of rebleeding of peptic ulcers.
Treatment of Zollinger Ellison Syndrome: Recommended Initial Dose: 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 esomeprazole 80-160 mg daily. With doses >80 mg daily, the dose should be divided and given twice daily.
Granules: Gastroesophageal Reflux Disease (GERD): Treatment of Endoscopically Proven Erosive Reflux Esophagitis: Children 1-11 years, weighing ≥10 to <20 kg: 10 mg once daily for 8 weeks, ≥20 kg: 10 mg or 20 mg once daily for 8 weeks.
Symptomatic Treatment of GERD: Children 1-11 years, weighing ≥10 kg: 10 mg once daily for up to 8 weeks.
Doses >1 mg/kg/day have not been studied.
Elderly: Dose adjustment is not required in the elderly.
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.
Tablet: For patients with severe liver impairment, a maximum dose of 20 mg.
Granules: For patients ≥12 years with severe liver impairment, a maximum dose of Nexium 20 mg should not be exceeded. For children 1-11 years with severe liver impairment, a maximum dose of 10 mg should not be exceeded (see Pharmacology: Pharmacokinetics under Actions).
Administration: Tablet: 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 ½ 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 the pellets immediately or within 30 min. Rinse the glass with ½ 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, see Instructions for Use, Handling and Disposal under Cautions for Usage.
Granules: For a 10-mg dose, empty the contents of a 10-mg sachet into a glass containing 15 mL water. For a 20-mg dose, empty the contents of two 10-mg sachets into a glass containing 30 mL water. Do not use carbonated water. Stir the contents until the granules have been dispersed and leave for a few minutes to thicken. Stir again and drink within 30 min. The granules must not be chewed or crushed. Rinse with 15 mL water to obtain all granules.
For patients who have a nasogastric or gastric tube in place, see Instructions for Use and Handling under Cautions for Usage, for preparation and administration instructions.
Overdosage
There is very limited experience to date with deliberate overdose. The symptoms described in connection with 280 mg were gastrointestinal symptoms and weakness. Single doses of esomeprazole 80 mg 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
Hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of Nexium.
Esomeprazole, like other PPIs, should not be administered with nelfinavir (see Interactions).
Special Precautions
In the presence of any alarm symptom (eg, significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with Nexium may alleviate symptoms and delay diagnosis.
Patients on long-term treatment (particularly those treated for >1 year) should be kept under regular surveillance. For granules, long-term treament is indicated in adults and adolescents ≥12 years (see Interactions).
Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. In granules, on-demand treatment has not been investigated in children and is, therefore, not recommended in this patient group. 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).
Nexium contains sucrose and glucose (for granules). Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Nexium.
Treatment with PPIs may lead to slightly increased risk of gastrointestinal infections eg, Salmonella and Campylobacter (see Pharmacology: Pharmacodynamics under Actions).
Co-administration of esomeprazole with atazanavir is not recommended (see Interactions). If the combination of atazanavir with a PPI is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with ritonavir 100 mg; 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 omeprazole (see Interactions). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.
Severe hypomagnesaemia has been reported in patients treated with PPIs like esomeprazole for at least 3 months, and in most cases for a year. Serious manifestations of hypomagnesaemia eg, 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 PPIs with medications eg, digoxin or drugs that may cause hypomagnesaemia (eg, diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically during treatment.
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.
Interference with Laboratory Tests: Increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be temporarily stopped for at least 5 days before CgA measurements.
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications eg, digoxin or drugs that may cause hypomagnesemia (eg, diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
Tablet: Pain or indigestion, vomiting blood or food, passing black (blood-stained) motions. Severe liver and kidney problems. Low magnesium levels in the blood. Triple therapy for eradication of H. pylori.
Effects on the Ability to Drive or Operate Machinery: No effects have been observed.
Use in pregnancy: For Nexium, clinical data on exposed pregnancies are insufficient. With the racemic mixture omeprazole, data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. 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 to pregnant women.
Use in lactation: 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.
Use In Pregnancy & Lactation
Use in pregnancy: For Nexium, clinical data on exposed pregnancies are insufficient. With the racemic mixture omeprazole, data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. 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 to pregnant women.
Use in lactation: 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.
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 very common ≥ 1/10; common ≥1/100, <1/10; uncommon ≥1/1,000, <1/100; rare ≥1/10,000, <1/1,000; very rare <1/10,000); not known (cannot be estimated from the available data).
Tablet: Blood and Lymphatic System Disorders: Rare: Leukopenia, thrombocytopenia. Very Rare: Agranulocytosis, pancytopenia.
Immune System Disorders: Rare: Hypersensitivity reactions eg, fever, angioedema and anaphylactic reaction/shock.
Metabolism and Nutrition Disorders: Uncommon: Peripheral oedema. Rare: Hyponatraemia. Not Known: Hypomagnesaemia; severe hypomagnesaemia can correlate with hypocalcaemia.
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: Rare: 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. Not Known: 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) .
Musculoskeletal and Connective Tissue 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.
Granules: General Disorders and Administration Site Conditions: Rare: Malaise, increased sweating.
Respiratory, Thoracic and Mediastinal Disorders: Rare: Bronchospasm.
Blood and Lymphatic System Disorders: Rare: Leukopenia, thrombocytopenia. Very Rare: Agranulocytosis, pancytopenia.
Nervous System Disorders: Common: Headache. Uncommon: Dizziness, paraesthesia, somnolence. Rare: Taste disturbance.
Immune System Disorders: Rare: Hypersensitivity reactions eg, fever, angioedema and anaphylactic reaction/shock.
Skin and Subcutaneous Tissue Disorders: Uncommon: Dermatitis, pruritus, rash, urticaria. Rare: Alopecia, photosensitivity. Very Rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).
Hepatobiliary Disorders: Uncommon: Increased liver enzymes. Rare: Hepatitis with or without jaundice. Very Rare: Hepatic failure, encephalopathy in patients with preexisting liver disease.
Gastrointestinal Disorders: Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting. Uncommon: Dry mouth. Rare: Stomatitis, gastrointestinal candidiasis. Not Known: Microscopic colitis.
Metabolism and Nutrition Disorders: Uncommon: Peripheral oedema. Rare: Hyponatraemia. Not Known: Hypomagnesaemia (see Precautions), severe hypomagnesaemia can correlate with hypocalcemia.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Fracture of the hip, wrist or spine (see Precautions). Rare: Arthralgia, myalgia. Very Rare: Muscular weakness.
Renal and Urinary Disorders: Very Rare: Interstitial nephritis.
Psychiatric Disorders: Uncommon: Insomnia. Rare: Agitation, confusion, depression. Very Rare: Aggression, hallucinations.
Reproductive System and Breast Disorders: Very Rare: Gynaecomastia.
Eye Disorders: Rare: Blurred vision.
Ear and Labyrinth Disorders: Uncommon: Vertigo.
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 intragastric acidity, the absorption of medicinal products eg, ketoconazole, itraconazole and erlotinib can decrease 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 2 out of 10 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 CYP2C19. 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 once daily) 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 once daily without omeprazole 20 mg once daily. Co-administration of omeprazole (40 mg once daily) 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 once daily). Treatment with omeprazole 20 mg once daily had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg once daily had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg once daily 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 eg, 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 esomeprazole 30 mg resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of esomeprazole 40 mg 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 esomeprazole 40 mg 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 international normalised ratio (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 coumarin derivatives.
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 Cmax 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 esomeprazole 40 mg resulted in a 32% increase in AUC and a 31% prolongation of elimination 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.
Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.
In a cross-over clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (day 1) and 42% (day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hrs) and 30% (day 5) when clopidogrel and omeprazole were administered together. In another study, it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this pharmacokinetic/pharmacodynamic interaction in terms of major cardiovascular events have been reported from observational and clinical studies.
Unknown Mechanism: When given together with PPIs, 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.
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possible leading to methotrexate toxicities. A temporary withdrawal of the PPI may be considered in some patients receiving treatments with high dose methotrexate.
Case reports, published population pharmacokinetic studies and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.
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 twice daily), 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. For granules, long-term treatment is indicated in adults and adolescents ≥12 years (see Indications).
Drugs known to induce CYP2C19 or CYP3A4 or both (eg, rifampicin and St. John’s wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.
Incompatibilities: Not applicable.
Caution For Usage
Instructions for Use, Handling and Disposal: Tablet: Administration Through Gastric Tube: Put the tablet into an appropriate syringe and fill the syringe with approximately 25 mL water and approximately 5 mL air.
For some tubes, dispersion in 50 mL water is needed to prevent the pellets from clogging the tube.
Immediately shake the syringe for approximately 2 min to disperse the tablet.
Hold the syringe with the tip up and check that the tip has not clogged.
Attach the syringe to the tube whilst maintaining the above position.
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).
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.
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.
Granules: For Patients who have a Nasogastric or Gastric Tube in Place: For a 10-mg dose, add the contents of a 10-mg sachet into 15 mL of water.
For a 20-mg dose, add the contents of a two 10-mg sachets into 30 mL of water. Stir.
Leave for a few minutes to thicken. Stir again.
Draw the suspension into a syringe.
Inject through the enteric tube, French size-6 or larger, into the stomach within 30 min after reconstitution.
Refill the syringe with 15 mL water for a 10-mg dose and 30 mL for a 20-mg dose.
Shake and flush any remaining contents from the enteric tube into the stomach.
Any unused suspension should be discarded.
Storage
Do not store above 30°C.
Shelf-Life: Granules: To be used 30 min after reconstitution.
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
FC tab 20 mg (gastro-resistant, 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 (gastro-resistant, 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. Gatro-resistant granules 10 mg (sachet, pale yellow, fine granules, brownish granules may be visible) x 28's.
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