Sompraz IV

Esomeprazole sodium.

SOMPRAZ IV is a sterile powder.
It is a white to off-white lyophilized cake.
Each vial contains Esomeprazole sodium 42.5 mg equivalent to esomeprazole 40 mg.
Excipients/Inactive Ingredients: Disodium edetate, Sodium hydroxide.

Pharmacotherapeutic group: Proton pump inhibitor. ATC code: A02B C05.
Pharmacology: Pharmacodynamics: Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.
Site and mechanism of action: Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+ K+ -ATPase - the acid pump and inhibits both basal and stimulated acid secretion.
Effect on gastric acid secretion: After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was reported to be 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 reported after oral administration of esomeprazole.
During intravenous administration of 80 mg esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/h for 23.5 hours, intragastric pH above 4, and pH above 6 was reported to be 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 reports in approximately 78% of patients after 4 weeks, and in 93% after 8 weeks of oral treatment.
In a reported randomized, double blind, placebo-controlled clinical study, 764 patients who presented with endoscopically confirmed peptic ulcer bleeding were randomized to receive esomeprazole solution for infusion (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either 80 mg esomeprazole as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for 72 hours. After the initial 72 hour period, all patients received 40 mg oral esomeprazole for 27 days for acid suppression. The reported occurrence of rebleeding within 3 days was 5.9% in the esomeprazole IV treated group compared to 10.3% for the placebo group (p=0.0256). At 7 and 30 days post-treatment, the reported occurrence of rebleeding in the esomeprazole treated versus the placebo treated group was 7.2% vs 12.9% (p=0.0096) and 7.7% vs 13.6%, respectively (p=0.0092).
Other effects related to acid inhibition: During reported 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 tumors. Literature reports report that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurements. Measurements should be reported if levels have not normalized by this time.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been reported in both children and adults during long term treatment with esomeprazole. The findings are considered to be of no clinical significance.
During reported long-term oral treatment with antisecretory drugs gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a psychological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile.
Pharmacokinetics: Distribution: The apparent volume of distribution at steady state in health is subjects is reported approximately 0.22 L/kg/body weight. Esomeprazole is 97% plasma protein bound.
Metabolism and excretion: Esomeprazole is reported to be completely metabolized by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.
The parameters as follows reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Reported 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 reported about 1.3 hours after repeated once-daily dosing. Total exposure (AUC) increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite.
Esomeprazole is reported to be completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.
Following repeated doses of 40 mg administered as intravenous injections, the mean peak plasma concentration is reported to be approx. 13.6 micromol/L. The mean peak plasma concentration after corresponding oral doses is reported to be approx. 4.6 micromol/L. A smaller increase (of approx. 30%) can be seen in the total exposure after intravenous administration compared to oral administration.
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 reported population lacks a functional CYP2C19 enzyme and is called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg oral esomeprazole, the mean total exposure was reported to be 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 reported for intravenous administration of esomeprazole. These findings have no implications for the posology of esomeprazole.
Metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Following a single oral dose of 40 mg esomeprazole the mean total exposure is reported to be approximately 30% higher in females than in males. No gender difference is reported after repeated once-daily administration. Similar differences of been reported for intravenous administration of esomeprazole. This findings have no implications for the posology of esomeprazole.
The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is reported to be decreased in patients with severe liver dysfunction resulting in a doubling of the total exposure of esomeprazole. Therefore, a maximum dose of 20 mg should not be exceeded in GERD patients with severe dysfunction. For patients with bleeding ulcers and severe liver impairment, following an initial bolus dose of 80 mg, a maximum continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its major metabolites do not report any tendency to accumulate with once-daily dosing.
No studies have been reported 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.

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

Gastric antisecretory treatment when the oral route is not possible: Patients who cannot take oral medication may be treated parenterally with 20-40 mg once daily. Patients with reflux oesophagitis should be treated with 40 mg once daily. Patients treated symptomatically for reflux disease should be treated with 20 mg once daily.
For healing of gastric ulcers associated with NSAID therapy the usual dose is 20 mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be treated with 20 mg once daily. Usually the IV treatment duration is short and transfer to oral treatment should be made as soon as possible.
Maintenance of haemostasis and prevention of rebleeding of gastric and duodenal ulcers: Following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers, 80 mg should be administered as a bolus infusion over 30 minutes, followed by a continuous intravenous infusion of 8 mg/h given over 3 days (72 hours).
The parenteral treatment period should be followed by acid-suppression therapy with esomeprazole 40 mg tablets once daily for 4 weeks.
Mode of Administration: Injection: 40 mg dose: The reconstituted solution should be given as an intravenous injection over a period of at least 3 minutes.
20 mg dose: Half of the reconstituted solution should be given as an intravenous injection over a period of approximately 3 minutes. Any unused solution should be discarded.
Infusion: 40 mg dose: The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
20 mg dose: Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded.
80 mg bolus dose: The reconstituted solution should be given as a continuous intravenous infusion over 30 minutes.
8 mg/h dose: The reconstituted solution should be given as a continuous intravenous infusion over a period of 71.5 hours (calculated rate of infusion of 8 mg/h).
Children and adolescents: Esomeprazole IV should not be used in children since no reported data is available.
Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Due to limited reported experience in patients with severe renal insufficiency, such patient should be treated with caution.
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 should not be exceeded.
Bleeding ulcer: 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 for infusion a continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient.
Elderly: Dose adjustment is not required in the elderly.

Overdose and Treatment: There is very limited experience to date with deliberate overdose. The symptoms described in connection with an oral dose of 280 mg were gastrointestinal symptoms and weakness. Reported single oral doses of 80 mg esomeprazole and intravenous doses of 308 mg esomeprazole over 24 hours were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilized.

Hypersensitivity to the active substance esomeprazole or to the other substituted benzimidazoles or to any of the excipients of this medicinal product.

In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with esomeprazole 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 reported a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%. Based on these reported data, concomitant use of esomeprazole and clopidogrel should be avoided (see Interactions).
Some reported 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 reported.
In reported randomized, double blind and controlled clinical studies on omeprazole and esomeprazole (including reported to 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 reported, 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 is not likely to affect the ability to drive or use machines.

Pregnancy: For esomeprazole limited reported data on exposed pregnancies are available. Reported animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Reported 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 esomeprazole to pregnant women.
Lactation: It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been reported. Therefore esomeprazole should not be used during breastfeeding.

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 reported clinical trials programme for esomeprazole and/or from reported post-marketing use. None was found to be dose-related.
Blood and lymphatic system disorders: Rare: Leukopenia, thrombocytopenia.
Very rare: Agranulocytosis, pancytopenia.
Immune system disorders: Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock.
Metabolism and nutrition disorders: Uncommon: Peripheral oedema.
Rare: Hyponatraemia.
Very rare: Hypomagnesaemia: severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also result in hypokalaemia.
Psychiatric disorders: Uncommon: Insomnia.
Rare: Agitation, confusion, depression.
Very rare: Aggression, hallucinations.
Nervous system disorders: Common: Headache.
Uncommon: Dizziness, paraesthesia, somnolence.
Rare: Taste disturbance.
Eye disorders: Uncommon: Blurred vision.
Ear and labyrinth disorders: Uncommon: Vertigo.
Respiratory, thoracic and mediastinal disorders: Rare: Bronchospasm.
Gastrointestinal disorders: Common: Abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting.
Uncommon: Dry mouth.
Rare: Stomatitis, gastrointestinal candidiasis.
Very rare: Microscopic colitis.
Hepatobiliary disorders: Uncommon: Increased liver enzymes.
Rare: Hepatitis with or without jaundice.
Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease.
Skin and subcutaneous tissue disorders: Common: Administration site reactions*.
Uncommon: Dermatitis, pruritus, rash, urticaria.
Rare: Alopecia, photosensitivity.
Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).
Musculoskeletal, connective tissue and bone disorders: Rare: Arthralgia, myalgia.
Very rare: Muscular weakness.
Renal and urinary disorders: Very rare: Interstitial nephritis.
Reproductive system and breast disorders: Very rare: Gynaecomastia.
General disorders and administration site conditions: Rare: Malaise, increased sweating.
*Administration site reactions have mainly been reported in a study with high-dose exposure over 3 days (72 hours). In the reported 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 reported that the clinical tissue irritation was concentration related.

Effects of esomeprazole on the pharmacokinetics of other drugs: The gastric acid suppression during treatment with esomeprazole IV and other PPIs may decrease or increase the absorption of drugs with a gastric pH dependent absorption. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole and erlotinib can decrease while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Reported 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 metabolizing enzyme. Reported concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance. Reported concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients; dose adjustment was not required in this reported study.
Reported concomitant administration of 40 mg esomeprazole to warfarin-treated patients show 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, reported 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 reported studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40%, and resulting in decreased maximum inhibition of (ADP induced) aggregation by an average of 14%.
It is, however, uncertain to what extent this interaction is clinically important. Reported one prospective, randomized (but incomplete) study (in over 3,760 patients comparing placebo with omeprazole 20 mg in patients treated with clopidogrel and ASA) and reported non-randomized, post-hoc analyses of data from large, prospective, randomized clinical outcome studies (in over 47,000 patients) did not show any evidence of an increased of risk for adverse cardiovascular outcome when clopidogrel and PPIs, including esomeprazole, were given concomitantly.
Results from a number of reported 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 reported 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 reported subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups, likely due to the concomitant administration of low dose ASA.
Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a reported 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, reported 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_½) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval reported after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole.
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 CYP2C19. 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 reported to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
Effects of other drugs on the pharmacokinetics of esomeprazole: Esomeprazole is metabolized by CYP2C19 and CYP3A4. Reported 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. Reported 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, those 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.

Incompatibilities: This medicinal product should not be used with other medicinal products except those mentioned in Instructions for use, handling and disposal as follows.
Instruction for use, handling and disposal: 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 20 mg dose, only half of the reconstituted solution should be used. Any unused solution should be discarded.
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 colorless to very slightly yellow.
The degradation of reconstituted solution is highly pH dependent and the product must therefore only be reconstituted in the specified volume of 0.9% sodium chloride for intravenous use. The reconstituted solution should not be mixed or co-administered in the same infusion set with any other drug.
Infusion: A solution for infusion is prepared by dissolving the content of one vial with esomeprazole in up to 100 ml 0.9% sodium chloride for intravenous use.
The reconstituted solution for infusion is clear and colourless to very slightly yellow.
Infusion 80 mg: A solution for infusion is prepared by dissolving the content of two vials of esomeprazole 40 mg in up to 100 ml of 0.9% sodium chloride for intravenous use.
The degradation of reconstituted solution is highly pH dependent and the product must therefore only be reconstituted in the specified volume of 0.9% sodium chloride for intravenous use.
The reconstituted solution should not be mixed or co-administered in the same infusion set with any other drug.
The reconstituted solution should be administered separately from other drugs.

Do not store above 30°C, protect from light.
Chemical and physical in-use stability has been demonstrated for 12 hours at 30°C. From a microbiological point of view, the products should be used immediately.

Antacids, Antireflux Agents & Antiulcerants

A02BC05 - esomeprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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