NEXIUM Esomeprazole Sodium 40mg Powder for IV Injection/Infusion 5mL 1's

Indications/Uses

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).
Nexium: Tablet: Esomeprazole (NEXIUM) tablets are indicated for: Patients requiring continued non-steroidal anti-inflammatory (NSAID) therapy: treatment of upper gastrointestinal symptoms associated with non-steroidal anti-inflammatory drug (NSAID) therapy; healing of gastric ulcers associated with non-steroidal anti-inflammatory drug (NSAID) therapy, including COX-2 selective NSAIDs; prevention of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory drug (NSAID) therapy, including COX-2 selective NSAIDs, in patients at risk.
Patients requiring continued low dose aspirin (75-325 mg) therapy: prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy, in patients at risk.
Following treatment with Esomeprazole (NEXIUM) IV: Maintenance of hemostasis and prevention of rebleeding of gastric or duodenal ulcers.
In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and; healing of Helicobacter pylori associated duodenal ulcer and; prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.
Pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion.
Granules: Esomeprazole (NEXIUM) oral suspension is primarily indicated for GERD in children 1-11 years old.
Esomeprazole (NEXIUM) oral suspension may also be used by patients having difficulty swallowing dispersed Esomeprazole (NEXIUM) tablets. For indications in patients from the age of 12 years reference is made to the Esomeprazole (NEXIUM) Tablet Prescribing Information.
Nexium IV: Esomeprazole (NEXIUM) I.V. is indicated as an alternative where oral therapy is not appropriate. I.V. therapy would constitute only part of a full treatment period for the following indications: Adults: Patients requiring continued non-steroidal anti-inflammatory (NSAID) therapy: for healing of gastric ulcers associated with NSAID therapy; for prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.
Esomeprazole (NEXIUM) I.V. is indicated for the short-term maintenance of hemostasis and prevention of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.
Children and adolescents aged 1-17 years: gastric antisecretory treatment when the oral route is not possible, such as: gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe symptoms of reflux.

Dosage/Direction for Use

Nexium: Children 1 - 11 years: Gastroesophageal Reflux Disease (GERD): Treatment of erosive reflux esophagitis: Weight <20 kg: 10 mg once daily for 8 weeks.
Weight ≥20 kg: 10 mg or 20 mg once daily for 8 weeks.
Long-term management of patients with healed esophagitis to prevent relapse: 10 mg once daily.
Symptomatic treatment of gastroesophageal reflux disease (GERD): 10 mg once daily for up to 8 weeks.
Doses over 1 mg/kg/day have not been studied.
Children 0 - 1 year: Gastroesophageal Reflux Disease (GERD): Treatment of gastroesophageal reflux disease (GERD) diagnostically confirmed through pH probe or endoscopy.
1 - 11 months: Weight 3 kg to 5 kg: 2.5 mg once daily for up to 6 weeks.
Weight > 5 kg to 7.5 kg: 5 mg once daily for up to 6 weeks.
Weight >7.5 kg to 12 kg: 10 mg once daily for up to 6 weeks.
Doses over 1.33 mg/kg/day have not been studied.
0 - 1 month: Weight > 2.5 kg: 2.5 mg once daily for up to 4 weeks.
Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution. (See Pharmacology: Pharmacokinetics under Actions.)
Impaired hepatic function: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum daily dose of 20 mg Esomeprazole (NEXIUM) should not be exceeded. (See Pharmacology: Pharmacokinetics under Actions.)
Tablet: The tablets should be swallowed whole with liquid.
They should not be chewed or crushed. The tablets can also be also dispersed in half a glass of non-carbonated water. No other liquids should be used. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.
For patients who cannot swallow, the tablet contents can be dispersed in non-carbonated water and administered through a gastric tube.
Adults: Gastroesophageal Reflux Disease (GERD): Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks.
An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.
Long-term management of patients with healed esophagitis to prevent relapse: 20 mg once daily.
Symptomatic treatment of GERD: 20 mg once daily in patients without esophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on demand regimen taking 20 mg once daily, when needed. In NSAID treated risk patients subsequent symptom control using on demand treatment is not recommended.
Patients requiring continued non-steroidal anti-inflammatory (NSAID) therapy: Treatment of upper gastrointestinal symptoms associated with NSAID therapy: 20 mg once daily in patients requiring NSAID therapy. If symptom control has not been achieved after 4 weeks, the patient should be further investigated.
Healing of gastric ulcers associated with NSAID therapy: 20 mg or 40 mg once daily for 4 to 8 weeks.
Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: 20 mg or 40 mg once daily.
Patients requiring continued low dose aspirin therapy: Prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk: 20 mg or 40 mg once daily.
Maintenance of hemostasis and prevention of rebleeding of gastric or duodenal ulcers following treatment with Esomeprazole (NEXIUM) IV: 40 mg once daily for 4 weeks. The oral treatment period should be preceded by acid-suppression therapy with Esomeprazole (NEXIUM) IV 80 mg administered as bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/hr given over 3 days (Refer to the Esomeprazole (NEXIUM) IV prescribing information as follows).
In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and: healing of Helicobacter pylori associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers: 20 mg Esomeprazole (NEXIUM) with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.
Pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion: The recommended initial dosage is Esomeprazole (NEXIUM) 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. Doses up to 120 mg twice daily have been administered.
Children 12 - 18 years: Gastroesophageal Reflux Disease (GERD): Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks.
An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.
Long-term management of patients with healed esophagitis to prevent relapse: 20 mg once daily.
Symptomatic treatment of gastroesophageal reflux disease (GERD): 20 mg once daily in patients without esophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily under medical supervision.
Treatment of duodenal ulcer caused by H. Pylori: When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents.
The treatment should be supervised by a specialist.
The dosage recommendation for esomeprazole is the following: 20 mg twice daily for one week.
Elderly: Dose adjustment is not required in the elderly.
Granules: The contents of a 10 mg sachet should be emptied into a container containing a tablespoon (15 mL) of non-carbonated water. Stir the contents and leave for a few minutes to thicken. Stir again and drink within 30 minutes. If any material remains after drinking, add more water, stir, and drink immediately. In cases where there is a need to use two sachets, they may be mixed in a similar way adding twice the required amount of water.
For patients who have a nasogastric or gastric tube in place, the contents of a 10 mg sachet can be added to a syringe containing 15 mL of water. Immediately shake the syringe and leave for a few minutes to thicken. Shake the syringe and inject through the nasogastric or gastric tube, French size 6 or larger, within 30 minutes. Refill the syringe with an equal amount of water (15 mL) and shake and flush any remaining contents from the nasogastric or gastric tube into the stomach.
Alternatively, the suspension can be prepared first and then drawn up into a syringe. Empty the contents of the 10 mg sachet into 15 mL of water. Stir and leave for a few minutes to thicken. Stir again and then draw the suspension into a syringe. Inject through the enteric tube, French size 6 or larger, into the stomach within 30 minutes after reconstitution. Refill the syringe with an equal amount of water (15 mL). Shake and flush any remaining contents from the enteric tube into the stomach.
Adults and adolescent from the age of 12 years: For dosage in patients from the age of 12 years, reference is made to the Esomeprazole (NEXIUM) Tablet Prescribing Information.
Nexium IV: Gastroesophageal Reflux Disease (GERD): Adults: Treatment with Esomeprazole (NEXIUM) I.V. can be given for up to 10 days as part of a full treatment period for the specified indications. When oral therapy is possible or appropriate, intravenous therapy with Esomeprazole (NEXIUM) I.V. should be discontinued and the therapy should be continued orally.
Treatment of erosive reflux esophagitis: 40 mg once daily.
Long-term management of patients with healed esophagitis to prevent relapse: 20 mg once daily.
Symptomatic treatment of gastroesophageal reflux disease: 20 mg once daily in patients without esophagitis.
Children: Treatment with Esomeprazole (NEXIUM) I.V. can be given as part of a full treatment period for GERD. When oral therapy is possible or appropriate, intravenous therapy with Esomeprazole (NEXIUM) I.V. should be discontinued, and the therapy should be continued orally. Dosing recommendations are provided in the table as follows. (See table.)




Patients requiring continued non-steroidal anti-inflammatory (NSAID) therapy: Healing of gastric ulcers associated with NSAID therapy: 20 mg once daily.
Prevention of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory (NSAID) therapy in patients at risk: 20 mg once daily.
Maintenance of hemostasis and prevention of rebleeding of gastric or duodenal ulcers: 80 mg administered as bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/hr given over 3 days.
The parenteral treatment period should be followed by acid-suppression therapy with Esomeprazole (NEXIUM) 40 mg orally once daily for 4 weeks (Refer to the Esomeprazole (NEXIUM) Tablet prescribing information - Dosage & Administration previously).
Method of administration: Injection (40 mg vial): A solution for injection (8mg/mL) is prepared by adding 5 mL of 0.9% sodium chloride for intravenous use to the vial.
40 mg dose: 5 mL of the reconstituted solution (8mg/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 (8mg/mL) should be given as an intravenous injection over a period of approximately 3 minutes.
10 mg dose (Children 1-11 years): 1.25 mL of the reconstituted solution (8 mg/mL) should be given as an intravenous injection over a period of at least 3 minutes.
1 mg/kg (Children 1-11 months*): A solution for injection (2 mg/mL) is prepared by adding 20 mL of 0.9% sodium chloride for intravenous use to the vial.
Calculate the volume of the reconstituted solution (2 mg/mL) for the required dose (1 mg/kg) and administer an intravenous injection over a period of at least 3 minutes.
0.5 mg/kg (Children 0-1 month*): A solution for injection (0.8 mg/mL) is prepared by adding 50 mL of 0.9% sodium chloride for intravenous use to the vial.
Calculate the volume of the reconstituted solution (0.8 mg/mL) for the required dose (0.5 mg/kg) and administer an intravenous injection over a period of at least 3 minutes.
*for definition of age for premature infants, see Pharmacology: Pharmacokinetics under Actions.
Infusion (40 mg vial): A solution for infusion is prepared by dissolving the content of one vial in up to 100 mL 0.9% sodium chloride for intravenous use.
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.
10 mg dose (Children 1-11 years): A quarter of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
1 mg/kg (Children 1-11 months*): Calculate the volume of the reconstituted solution for the required dose (1 mg/kg) and administer as an intravenous infusion over a period of 10 to 30 minutes.
0.5 mg/kg (Children 0-1 month*): Calculate the volume of the reconstituted solution for the required dose (0.5 mg/kg) and administer as an intravenous infusion over a period of 10 to 30 minutes.
*for definition of age for premature infants, see Pharmacology: Pharmacokinetics under Actions.
Continuous Infusion (40 mg vial): A solution for infusion is prepared by dissolving the content of two vials of esomeprazole 40 mg in up to 100 mL of 0.9% Sodium Chloride for intravenous use.
80 mg bolus dose: The reconstituted solution containing 80 mg esomeprazole should be given as a continuous intravenous infusion over 30 minutes.
8mg/hr 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/hr).
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 Esomeprazole (NEXIUM) I.V. should not be exceeded.
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 Esomeprazole (NEXIUM) I.V., a continuous intravenous infusion dose of 4 mg/hr may be sufficient to maintain adequate acid control (see Pharmacology: Pharmacokinetics under Actions).
Elderly: Dose adjustment is not required in the elderly.

Overdosage

The symptoms described in connection with deliberate Esomeprazole (NEXIUM) overdose (limited experience of oral doses in excess of 240 mg/day) are transient. Single oral doses of 80 mg and intravenous doses of 308 mg Esomeprazole (NEXIUM) over 24 hrs were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilized.

Administration

May be taken with or without food: Tab: Swallow whole w/ liqd. Do not chew/crush. May also be dispersed in ½ glass of non-carbonated water. No other liqd should be used. Stir until the tab disintegrate & drink the liqd w/ the pellets immediately or w/in 30 min. Rinse the glass w/ ½ glass of water & drink. Do not chew/crush the pellets. For patients who cannot swallow, the tab contents can be dispersed in non-carbonated water & administered through a gastric tube. Granules: Empty contents of a 10 mg sachet into a container w/ 1 tbsp of non-carbonated water & stir. Leave for a few min to thicken. Stir again & take w/in 30 min. Rinse remaining contents w/ water & drink immediately. For patients who cannot swallow, the mixt can be administered through a nasogastric tube (≥6 French) w/ a syringe w/in 30 min. Refill syringe w/ 15mL of water, shake & flush any remaining contents from the nasogastric tube.

Contraindications

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

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 Esomeprazole (NEXIUM/NEXIUM IV) may alleviate symptoms and delay diagnosis.
Concomitant administration with esomeprazole and drugs such as atazanavir and nelfinavir is not recommended (see Interactions).
Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%. Based on these data, concomitant use of esomeprazole and clopidogrel should be avoided. See also Interactions.
Some published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with a small increased risk for osteoporosis related fractures. However, in other similar observational studies no such increased risk was found.
In AstraZeneca's randomized, double-blind and controlled clinical studies on omeprazole and esomeprazole (including two open long-term studies of up to more than 12 years) there are no indications that PPIs are associated with osteoporotic fractures.
Although a causal relationship between omeprazole/esomeprazole and osteoporotic fractures has not been established, patients at risk for developing osteoporosis or osteoporotic fractures are advised to have appropriate clinical monitoring in accordance with current clinical guidelines for these conditions.
Effects on ability to drive and use machines: Esomeprazole (NEXIUM/NEXIUM IV) is not likely to affect the ability to drive or use machines.
Nexium: 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 (NEXIUM) 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 (NEXIUM) 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.
Granules: This medicinal product contains sucrose and glucose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Use In Pregnancy & Lactation

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

Adverse Reactions

The following definitions of frequencies are used: Common ≥1/100, Uncommon ≥1/1000 and <1/100, Rare ≥ 1/10000 and <1/1000, Very rare <1/10000.
The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole and/or from post-marketing use. None was found to be dose-related.
Blood and lymphatic system disorders: Rare: Leukopenia, thrombocytopenia.
Very rare: Agranulocytosis, pancytopenia.
Immune system disorders: Rare: Hypersensitivity reactions eg, angioedema and anaphylactic reaction/shock.
Metabolism and nutrition disorders: Uncommon: Peripheral oedema.
Rare: Hyponatraemia.
Very Rare: Hypomagnesaemia; severe hypomagnesaemia may result in hypocalcaemia.
Hypomagnesaemia may also result in hypokalaemia.
Psychiatric disorders: Uncommon: Insomnia.
Rare: Agitation, confusion, depression.
Very rare: Aggression, hallucination.
Nervous system disorders: Common: Headache.
Uncommon: Dizziness, paraesthesia, somnolence.
Rare: Taste disturbance.
Eye disorders: Rare: Blurred vision.
Ear and labyrinth disorders: Uncommon: Vertigo.
Respiratory, thoracic and mediastinal disorders: Rare: Bronchospasm.
Gastrointestinal disorders: Common: Abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation.
Uncommon: Dry mouth.
Rare: Stomatitis, gastrointestinal candidiasis.
Very rare: Microscopic colitis.
Hepatobiliary disorders: Uncommon: Increased liver enzymes.
Rare: Hepatitis with or without jaundice.
Very rare: Hepatic failure, hepatic encephalopathy.
Skin and subcutaneous tissue disorders: Uncommon: Dermatitis, pruritus, urticaria, rash.
Common: Administration site reactions*
Rare: Alopecia, photosensitivity.
Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal, connective tissue and bone disorders: Rare: Arthralgia, myalgia.
Very rare: Muscular weakness.
Renal and urinary disorders: Very rare: Interstitial nephritis.
Reproductive system and breast disorders: Very rare: Gynaecomastia.
General disorders and administration site conditions: Rare: Malaise, hyperhidrosis.
*FOR NEXIUM IV ONLY. Administration site reactions have mainly been observed in a study with high-dose exposure over 3 days (72 hours). In the non-clinical program for esomeprazole intravenous formulation there was no evidence of vaso-irritation but a slight tissue inflammatory reaction at the injection site after subcutaneous (paravenous) injection was noted. The non-clinical findings somewhat indicated that the clinical tissue irritation was concentration related.

Drug Interactions

Effects of esomeprazole on the pharmacokinetics of other drugs: The gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of drugs with a gastric pH dependent absorption. Like with other drugs that decrease the intragastric acidity, the absorption of drugs, such as ketoconazole, itraconazole and erlotinib can decrease while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).
Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance. Concomitant oral administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients; dose adjustment was not required in this study. Concomitant oral administration of 40 mg esomeprazole to warfarin-treated patients showed that, despite a slight elevation in the trough plasma concentration of the less potent R-isomer of warfarin, the coagulation times were within the accepted range. However, from post marketed use cases of elevated INR of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when initiating and ending treatment with warfarin or other coumarin derivatives.
Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%.
It is, however, uncertain to what extent this interaction is clinically important. One prospective, randomized (but incomplete) study (in over 3760 patients comparing placebo with omeprazole 20 mg in patients treated with clopidogrel and ASA) and non-randomized, post-hoc analyses of data from large, prospective, randomized clinical outcome studies (in over 47000 patients) did not show any evidence of an increased risk for adverse cardiovascular outcome when clopidogrel and PPIs, including esomeprazole, were given concomitantly.
Results from a number of observational studies are inconsistent with regard to increased risk or no increased risk for CV thromboembolic events when clopidogrel is given together with a PPI.
When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups, likely due to the concomitant administration of low dose ASA.
Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C_max and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
In healthy volunteers, concomitant oral administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t_1/2) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole (see also Precautions).
Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus.
When given together with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.
Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. For other antiretroviral drugs, such as saquinavir, increased serum levels have been reported. There are also some antiretroviral drugs for which unchanged serum levels have been reported when given with omeprazole. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and antiretroviral drugs such as atazanavir and nelfinavir is not recommended.
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
Nexium: Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interaction.
Effects of other drugs on the pharmacokinetics of esomeprazole: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant 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, such as voriconazole, may result in more than doubling of the esomeprazole exposure. However, dose adjustment of esomeprazole is not required in either of these situations.
Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Caution For Usage

Incompatibilities: Nexium: Granules: Not applicable.
Nexium IV: The degradation of the reconstituted solution is highly pH dependent and the product must therefore only be reconstituted with 0.9% sodium chloride for intravenous use according to the instructions in Dosage & Administration. The reconstituted solution should not be mixed or co-administered in the same infusion set with any other drug.
Instructions for use and handling: Nexium: Granules: No special requirements.
Nexium IV: The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Only clear solution should be used.
For single use only.
When administering a 20mg dose only half of the reconstituted solution should be used. Any unused solution should be discarded.
The reconstituted solution should be used within 12 hours. From a microbiological point of view, the product should be used immediately. Do not store above 30°C.
Injection: A solution for injection is prepared by adding 5 mL of 0.9% sodium chloride for intravenous use to the vial with esomeprazole. The reconstituted solution for injection is clear and colourless to very slightly yellow.
Infusion: A solution for infusion is prepared by dissolving the content of one vial with esomeprazole in up to 100mL 0.9% sodium chloride for intravenous use. The reconstituted solution for infusion is clear and colourless to very slightly yellow.

Storage

Store at a temperature not exceeding 30°C.
Nexium: Tablet: Store in the original package (blister).
Nexium IV: Special precautions for storage: Esomeprazole (NEXIUM) I.V. should be stored at room temperature in the outer container which it is provided in, since this protects the vial from light. Vials can be stored exposed to normal in-door light, for up to 24 hours outside the box.
Reconstituted solution for injection and infusion: Chemical, physical and microbiological in-use stability of the reconstituted solution has been demonstrated for 12 hours. The reconstituted solution can be kept in normal in-door light at up to 30°C.

Action

Pharmacology: Pharmacodynamics: Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.
Site and mechanism of action: Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H⁺K⁺-ATPase - the acid pump and inhibits both basal and stimulated acid secretion.
Effect on gastric acid secretion: Nexium: After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for 5 days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6 - 7 hours after dosing on day 5.
After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
Following repeated dose administration of 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, the effect on intragastric pH, expressed as change in percentage of time with intragastric pH>4 from baseline, is similar to that observed after esomeprazole 20 mg in adults. In addition, 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, results in a significant reduction in esophageal acid exposure.
Nexium IV: 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/hr for 23.5 hours, intragastric pH above 4, and pH above 6 was maintained for a mean time of 21 hours, and 11-13 hours, respectively, over 24 hours in healthy subjects.
Therapeutic effects of acid inhibition: Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks, and in 93% after 8 weeks of oral treatment.
Nexium: 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 (non US).
After eradication treatment there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
In a randomised, double blind, placebo controlled clinical study, 764 patients received 80 mg bolus followed by continuous intravenous infusion of Esomeprazole (NEXIUM) IV for 71.5 hrs followed by continued treatment for 27 days with oral Esomeprazole (NEXIUM) 40 mg. At 7 and 30 days post-treatment, the occurrence of rebleeding was 7.2% in the treatment group vs. 12.9% in the placebo group and 7.7% vs. 13.6%, respectively.
Nexium IV: In a randomized, double blind, placebo-controlled clinical study, 764 patients with bleeding gastric or duodenal ulcers were randomized to receive Esomeprazole (NEXIUM) I.V. for Injection (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either 80 mg Esomeprazole (NEXIUM) I.V. administered as bolus infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for 72 hrs. After the initial 72 hour period, all patients received oral Esomeprazole (NEXIUM) 40 mg for 27 days for acid suppression. The occurrence of rebleeding within 3 days was 5.9% in the treatment group compared to 10.3% for the placebo group. At 7 and 30 days post-treatment, the occurrence was 7.2% vs 12.9% and 7.7% vs 13.6%, respectively.
Other effects related to acid inhibition: During treatment with antisecretory drugs serum gastrin increases, in response to the decreased acid secretion. Also chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Literature reports indicate that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurement. Measurements should be repeated if levels have not normalised by this time.
An increased number of ECL cells, possibly related to the increased serum gastrin levels, have been observed in both children and adults during long term treatment with 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 hospitalized patients, possibly also Clostridium difficile.
Comparative Clinical Trials: In a five-way crossover study, the 24 hour intragastric pH profile of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg once daily was evaluated in 24 symptomatic GERD patients. On day 5, intragastric pH was maintained above 4.0 for a mean of 15.3 hours with esomeprazole, 13.3 hours with rabeprazole, 12.9 hours with omeprazole, 12.7 hours with lansoprazole and 11.2 hours with pantoprazole (p≤0.001 for differences between esomeprazole and all other comparators). Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 4.0 for more than 12 hours relative to the other proton pump inhibitors (p <0.05).
Nexium: Patients requiring continued NSAID therapy: Treatment of NSAID associated upper gastrointestinal symptoms: Esomeprazole (NEXIUM) was significantly better than placebo in treatment of upper gastrointestinal symptoms in patients using either non-selective or COX-2-selective NSAIDs.
Healing of gastric ulcers associated with NSAID therapy: Esomeprazole (NEXIUM) was significantly better than ranitidine in healing of gastric ulcers in patients using NSAIDs, including COX-2-selective NSAIDs.
Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: Esomeprazole (NEXIUM) was significantly better than placebo in prevention of gastric and duodenal ulcers associated with NSAID therapy in patients using NSAIDs, including COX-2-selective NSAIDs.
Patients requiring continued low dose aspirin therapy: Prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk.
Esomeprazole (NEXIUM) was significantly better than placebo in prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk (prior history of ulcer disease, age ≥60 years with a history of coronary artery disease or age ≥65 years).
Nexium IV: Paediatric population: Following repeated oral dose administration of 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, the effect on intragastric pH, expressed as change in percentage of time with intragastric pH>4 from baseline, is similar to that observed after esomeprazole 20 mg in adults. In addition, 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, results in a significant reduction in oesophageal acid exposure.
Pharmacokinetics: Absorption and distribution: Nexium: 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.
Distribution: Nexium IV: 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 as follows reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, ie, extensive metabolisers.
Total plasma clearance is about 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance, probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. Esomeprazole is completely eliminated from plasma between doses, with no tendency for accumulation during once-daily administration.
The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Special patient populations: Nexium: Approximately 3% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%.
These findings have no implications for the dosage of Esomeprazole (NEXIUM).
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Following a single dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the dosage of Esomeprazole (NEXIUM).
The metabolism of esomeprazole in patients with mild to moderate liver impairment may be impaired. The metabolic rate is decreased in patients with severe liver impairment resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe hepatic impairment. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.
No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Following repeated dose administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (t_max) in 12 to 18 year-olds was similar to that in adults for both esomeprazole doses.
Following repeated dose administration of 10 mg and 20 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (t_max) for the 10 mg dose was similar across the 1 to 11 years-olds and similar to the total exposure seen with the 20 mg dose in 12 to 18 year-olds and adults. The 20 mg dose resulted in higher exposure in 6 to 11 year-olds compared to 12 to 18 year-olds and adults.
Repeated dose administration of 5 mg esomeprazole resulted in insufficient exposure in 1 to 5 year-olds.
Following repeated dose administration of 1.0 mg/kg esomeprazole in 1 to 11 month old infants, the exposure (AUC) was slightly higher than that observed after 0.5 mg/kg esomeprazole in < 1 month old infants, but similar to that observed after 10 mg in 1 to 11 year-olds, and 20 mg in 12 to 18 year-olds as well as adults.
Nexium IV: CYP2C19 enzyme deficiency: Approximately 3% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily oral administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve 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 dosage of esomeprazole.
Age and sex: The metabolism of esomeprazole is not significantly changed in elderly subjects (71 to 80 years of age).
Following a single oral dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. Similar differences have been seen for intravenous administration of esomeprazole. These findings have no implications for the dosage of esomeprazole.
The pharmacokinetics of esomeprazole in children and adolescents was related to body weight and age (see "Paediatric population" as follows).
Renal insufficiency: 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.
Hepatic insufficiency: The metabolism of esomeprazole in patients with mild to moderate liver impairment may be impaired. The metabolic rate is decreased in patients with severe liver impairment resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in GERD patients with severe impairment. 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/hr may be sufficient in patients with bleeding ulcers. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.
Paediatric population: In a randomized, open-label, multi-national, repeated dose study, esomeprazole was given as a once-daily 3-minute injection in a total of 50 paediatric patients 0 to 17 years old to evaluate the pharmacokinetics of esomeprazole.
The exposure to esomeprazole observed after I.V. esomeprazole 0.5 mg/kg in 0 to 1 month old patients* was lower than that observed with 1.0 mg/kg in 1 to 11 month olds, but similar to that observed with 10 mg in 1 to 5 year olds, 10 mg in 6 to 11 year olds and 20 mg in 12 to 17 year olds. The exposure levels with these doses were higher than that observed with 20 mg Esomeprazole (NEXIUM) I.V. in adults but lower than that with 40 mg Esomeprazole (NEXIUM) I.V. in adults. The exposure to esomeprazole observed after I.V. esomeprazole 1.0 mg/kg in 1 to 11 month olds, 20 mg in 6 to 11 year old patients and 40 mg in 12 to 17 year old patients was similar to that observed with 40 mg Esomeprazole (NEXIUM) I.V. in adults. Model based predictions indicate that C_ss,max following I.V. administration of esomeprazole as a 10-minute, 20-minute and 30-minute infusions will be reduced by on average 37% to 49%, 54% to 66% and 61% to 72%, respectively, across all age and dose groups compared to when the dose is administered as a 3-minute injection.
* A patient in the age group 0 up to 1 month was defined as a patient with a corrected age of ≥32 complete weeks and < 44 complete weeks, where corrected age was the sum of the gestational age and the age after birth in complete weeks. A patient in the age group 1 to 11 months had a corrected age of ≥44 complete weeks.
Toxicology: Preclinical safety data: Nexium: Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.
There was no unexpected toxicity and/or other effects following esomeprazole treatment of rats or dogs from the neonatal period, during suckling and beyond weaning, compared to those previously observed in adult animals. Neither were there any findings indicating that neonatal/juvenile animals are more susceptible to proliferative changes in the gastric mucosa following esomeprazole treatment. Thus, there were no findings in these juvenile toxicity studies that indicate any specific risk in the pediatric population.
Nexium IV: Preclinical studies reveal no particular hazard for humans, based on conventional studies of single and repeated dose toxicity, embryo-foetal toxicity and mutagenicity. As in the oral studies, repeated intravenous administration of esomeprazole to animals resulted in few and primarily mild effects. However, very high intravenous doses caused an acute toxic response that consisted of occasional, nonspecific and short-lived CNS signs. This effect appeared to be associated with the C_max rather than the AUC of esomeprazole. Comparison of the C_max values obtained in humans given 40 mg esomeprazole as a 3-minute injection and the plasma concentrations that were acutely toxic in animals showed a wide margin of safety (at least 6-fold for total and 20-fold for unbound plasma concentrations).
The C_max following a 30 minute infusion of 80 mg esomeprazole in man was very similar to that seen after 40 mg given over 30 minutes. Similar safety margins between the C_max levels in animals and man were seen (at least 5.5-fold for the total and 18-fold for the unbound plasma concentrations).
Comparison of the esomeprazole exposure obtained during continuous intravenous infusion of 8 mg/hr for up to 3 days in man and in continuous infusion of high intravenous doses in dogs for up to 1 month also showed good safety margins: 4.6-fold for the total and 15-fold for the unbound plasma concentrations at steady state (C_ss) and 36-fold for the total and 120-fold for the unbound AUC values over the complete infusion period.
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.

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Antacids, Antireflux Agents & Antiulcerants