INSTRUCTION

for medical use of the medicinal product

 

ESOZOL

 

Composition:

active substance: esomeprazole;

1 vial contains esomeprazole sodium 42.55 mg equivalent to esomeprazole 40 mg;

excipients: disodium edetate, sodium hydroxide.

 

Pharmaceutical form. Lyophilisate for solution for injection and infusion.

Basic physic-chemical properties: white or almost white powder.

 

Pharmacotherapeutic group. Drugs for peptic ulcers. Proton pump inhibitors.

ATC code A02B C05.

 

Pharmacological properties.

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.

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 esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The effect is similar irrespective of whether esomeprazole is administered orally or intravenously.

Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown after oral administration of esomeprazole.

During intravenous administration of 80 mg esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/h for 23.5 hours, intragastric pH above 4, and pH above 6 was maintained for a mean time of 21 hours, and 11-13 hours, respectively, over 24 hours in healthy subjects.

Therapeutic effects of inhibition of acid secretion

Healing of reflux oesophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks, and in 93% after 8 weeks of oral treatment.

Other effects associated with inhibition of acid secretion

During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion.

Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5–14 days prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.

An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients during long-term therapy with esomeprazole.

During long-term oral treatment with antisecretory medicinal products gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitor increases the risk of gastrointestinal infections (e.g. Salmonella, Campilobacter or Clostridium difficile) in hospitalised patients.

Children

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 orally 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 <1 month), efficacy and safety in patients with symptoms of GERD were evaluated. Esomeprazole 0.5 mg/kg once daily was given orally 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 to 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.

In a study in paediatric GERD patients (<1 to 17 years of age) receiving long-term PPI treatment, 61% of the children developed minor degrees of ECL cell hyperplasia with no known clinical significance and with no development of atrophic gastritis or carcinoid tumours.

 

Pharmacokinetics.

Distribution

The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 l/kg body weight. Esomeprazole is 97% plasma protein bound.

Biotransformation and Elimination

Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.

The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme (extensive metabolisers).

Total plasma clearance is about 17 l/h after a single dose and about 9 l/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once daily dosing. Total exposure (AUC) increases with repeated administration of esomeprazole. This increase is dose dependent and results in a non-linear dose- AUC relationship after repeated administration. This time and dose dependency is due to a decrease of first-pass metabolism and systemic clearance probably caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite.

Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration.

Following repeated doses of 40 mg administered as intravenous injections, the mean peak plasma concentration is approximately 13.6 micromol/l. A smaller increase (of approximately 30%) can be seen in total exposure after intravenous administration compared to oral administration.

The major metabolites of esomeprazole have no effect on gastric acid secretion.

There is a dose-linear increase in total exposure following intravenous administration of esomeprazole as a 30-minute infusion (40 mg, 80 mg or 120 mg) followed by a continuous infusion (4 mg/h or 8 mg/h) over 23.5 hours.

Special patient populations

Poor metabolizers

About 2.9 ±1.5% of the population lacks a functional CYP2C19 enzyme and is called poor metabolisers. In these individuals, the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once daily administration of 40 mg oral esomeprazole, the mean total exposure was approximately 100% higher in 'poor metabolisers' than in subjects with a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%. Similar differences have been seen for intravenous administration of esomeprazole. These findings have no implications for the posology of esomeprazole.

Elderly

The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).

Gender

Following a single oral dose of 40 mg esomeprazole the mean total exposure is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. Similar differences have been observed for intravenous administration of esomeprazole. These findings have no implications for the posology of esomeprazole.

Hepatic impairment

The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the total exposure of esomeprazole. Therefore, a maximum dose of 20 mg should not be exceeded in GERD patients with severe dysfunction. For patients with bleeding ulcers and severe liver impairment, following an initial bolus dose of 80 mg, a maximum continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its major metabolites do not show any tendency to accumulate with once daily dosing.

Renal impairment

No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole, but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.

Children

In a randomised, open-label, multi-national, repeated dose study, esomeprazole was given as a once daily 3-minute injection over four days. The study included a total of 59 paediatric patients 0-18 years old of which fifty patients (7 children in the age group 1 to 5 years) completed the study and were evaluated for the pharmacokinetics of esomeprazole.

The table below describes systemic exposure to esomeprazole following the intravenous administration as a 3-minute injection in paediatric patients and adult healthy subjects. The values in the table are geometric means (range). The 20 mg dose for adults was given as a 30-minute infusion. The С_ss, max was measured 5-minutes post dose in all paediatric groups and 7 minutes post-dose in adults on the 40 mg dose, and after stop of infusion in adults on the 20 mg dose.

Table 1

Age group	Dosage group	AUC (μmol*h/l)	Сss, max (μmol/l)
0–1 month*	0.5 mg/kg (n = 6)	7.5 (4.5–20.5)	3.7 (2.7–5.8)
1–11 month*	1.0 mg/kg (n = 6)	10.5 (4.5–22.5)	8.7 (4.5–14.0)
1–5 years	10 mg (n = 7)	7.9 (2.9–16.6)	9.4 (4.4–17.2)
6–11 years	10 mg (n = 8)	6.9 (3.5–10.9)	5.6 (3.1–13.2)
	20 mg (n = 8)	14.4 (7.2–42.3)	8.8 (3.4–29.4)
	20 mg (n = 6)**	10.1 (7.2–13.7)	8,1 (3.4–29.4)
12–17 years	20 mg (n = 6)	8.1 (4.7–15.9)	7.1 (4.8–9.0)
	40 mg (n = 8)	17.6 (13.1–19.8)	10.5 (7.8–14.2)
Adults	20 mg (n = 22)	5.1 (1.5–11.8)	3.9 (1.5–6.7)
	40 mg (n = 41)	12.6 (4.8–21.7)	8.5 (5.4–17.9)

* 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.

** Two patients excluded, one most likely a CYP2C19 poor metaboliser and one on concomitant therapy with a CYP3A4 inhibitor.

Model-based predictions indicate that C_{ss, max} following intravenous 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.

 

Clinical particulars.

Indications.

Adults

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 Nonsteroidal Anti-inflammatory drug NSAIDs) therapy;
• - prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.

Short-term maintenance of haemostasis and prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.

Children over 1 to 18 years of age

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.

 

Contraindications.

Hypersensitivity to esomeprazole, to substituted benzimidazoles or to any of the excipients.

Esozol, like other proton pump inhibitors, should not be used concomitantly with atazanavir, nelfinavir (see “Interaction with other medicinal products and other forms of interaction”).

 

Interactions with other medicinal products and other forms of interaction.

Data on drug interactions are based on adult patients studies only.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Medicinal products with pH dependent absorption

Gastric acid suppression during treatment with esomeprazole may increase or decrease the absorption of medicinal products, if the mechanism of their absorption is affected by gastric acidity.

As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as 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 two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic medicinal product monitoring of digoxin should then be reinforced.

Protease inhibitors

Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of 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, C_max, C_mіn). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure.

The co-administration of omeprazole (20 mg qd) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/100 mg ritonavir qd without omeprazole 20 mg qd. Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, C_max and C_min by 36-39% and meanAUC, C_max and C_min for the pharmacologically active metabolite M8 was reduced by 75-92%.

Proton pump inhibitors, including esomeprazole, should not be co-administered with atazanavir and nelfinavir.

For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg qd). Treatment with omeprazole 20 mg qd had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg qd had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg qd had no effect on the exposure of lopinavir (with concomitant ritonavir). Due to the similar pharmacodynamics effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated.

Medicinal products metabolised by CYP2C19

Esomeprazole inhibits CYP2C19, the major esomeprazole metabolizing enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentration of these medicinal products may be increased and a dose reduction could be needed. No in-vivo interaction studies have been performed with high-dose intravenous regimen (80 mg + 8 mg/h). The effect of esomeprazole on medicinal products metabolised by CYP2C19 may be more pronounced during this regimen and patients should be monitored closely for adverse effects during the 3-day intravenous treatment.

Diazepam

Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.

Phenytoin

Concomitant oral administration of 40 mg esomeprazole and phenytoin in a 13% increases in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

Voriconazole

Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUCτ of by 15% and 41% respectively.

Cilostazol

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 C_max and AUC for cilostazol by 18% and 26% respectively and one of its active metabolites by 29% and 69%, respectively.

Warfarin

Concomitant oral administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, according to post-marketing experience of oral esomeprazole, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.

Cisapride

In healthy volunteers, concomitant oral administration of 40 mg esomeprazole and cisapride resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t ½), 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.

Tacrolimus

Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed and dosage of tacrolimus adjusted if needed.

Methotrexate

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.

Clopidogrel

Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40% and resulting in decreased maximum inhibition of (ADP-induced) platelet aggregation by 14%.

When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP-induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + combined (esomeprazole + ASA) product groups. Inconsistent data on the clinical implications of a PK / PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. Concomitant use of esomeprazole and clopidogrel should be avoided.

Investigated medicinal products with no clinically relevant interaction

Amoxicillin or quinidine

Esomeprazole has been shown to have no clinically relevant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Effects of other medicinal products 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 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC of 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.

Medicinal products which induce CYP2C19 and/or CPY3A4

Medicinal products 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.

Paediatric population

Interaction studies have been performed only in adults.

 

Precautions for use.

In the presence of any alarming symptoms (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.

Gastrointestinal infections

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section "Pharmacodynamics").

Absorption of vitamin B₁₂

Esomeprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B₁₂ (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B₁₂ absorption on long-term therapy.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like esomeprazole, for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Risk of fracture

Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), may moderately increase the risk of hip, wrist and spine fractures, 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.

Subacute cutaneous lupus erythematosus

Proton pump inhibitors are associated with very infrequent cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping esomeprazole. Subacute cutaneous lupus erythematosus after previous treatment with a proton pump inhibitor may increase the risk of subacute cutaneous lupus erythematosus with other proton pump inhibitors.

Combination with other medicines

Co-administration of esomeprazole with atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").  If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded.

Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with medicinal products metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and esomeprazole (see section "Interaction with other medicinal products and other forms of interaction"). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole with clopidogrel should be discouraged.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

Each vial contains less than 1 mmol of sodium, i.e. Esozol is practically free of sodium.

 

Pregnancy and lactation.

There are limited data on using Esozol during pregnancy. 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. However, caution should be exercised when prescribing to pregnant women..

Clinical data on exposed pregnancies with esomeprazole are insufficient. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity of esomeprazole.

Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect fertility.

Breast-feeding

It is not known whether esomeprazole is excreted in human breast milk. No studies have been performed in breast-feeding women. Esozol should not be used during breast-feeding.

Fertility

The results of animal studies with omeprazole racemic mixtures do not indicate the effect of omeprazole on fertility in the case of oral administration of the drug.

 

Effects on ability to drive and use machines.

Esomeprazole has minor influence on the ability to drive and use machines. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported (see section "Adverse reactions"). If affected, patients should not drive or use machines.

 

Method of administration and dosage.

Dosage

Adults

Gastric antisecretory treatment when the oral route is not possible

Patients who cannot take oral medication may be treated parenterally with 20-40 mg once daily.

Patients with reflux oesophagitis should be treated with 40 mg once daily. Patients treated symptomatically for reflux disease should be treated with 20 mg once daily.

For healing of gastric ulcers associated with NSAID therapy, the usual dose is 20 mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be treated with 20 mg once daily.

Usually the intravenous treatment duration is short and transfer to oral treatment should be made as soon as possible.

Short-term 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 oral acid suppression therapy for 4 weeks.

Method of administration

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.

If the entire reconstituted content of the vial is not required, any unused solution should be disposed of in accordance with local requirements.

The reconstituted solution for injection and infusion is clear and colourless to very slightly yellow.

Injection

Esozol 40 mg is given as an intravenous injection over 3 minutes. The solution for injection is prepared by adding 5 ml of 0.9% sodium chloride solution to the vial of esomeprazole. Half of the reconstituted solution is used to administer a dose of 20 mg. Any unused solution should be discarded.

40 mg dose

Esozol 40 mg should be given as an intravenous infusion over a period of 10 to 30 minutes. The solution for infusion is prepared by dissolving the contents of one vial of 40 mg esomeprazole in 100 ml of 0.9% sodium chloride for intravenous use.

20 mg dose

Half of the reconstituted solution is used to administer a dose of 20 mg. Any unused solution should be discarded.

Bolus infusion 80 mg

The solution for 80 mg infusion is prepared by dissolving the contents of two vials of 40 mg of esomeprazole in a volume of up to 100 ml of 0.9% sodium chloride for intravenous use.

The reconstituted solution should be given as a continuous intravenous infusion over 30 minutes.

8 mg/min dose

The reconstituted solution should be given as a long-term intravenous infusion over a period of 72 hours (calculated for 8 mg/h infusion rate).

Special populations

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution (see section "Pharmacokinetics").

Hepatic impairment

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 (see section "Pharmacokinetics").

Bleeding ulcers: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, following an initial intravenous dose of 80 mg esomeprazole for 30 minutes, a continuous intravenous infusion dose of 4 mg/h for 72 hours may be sufficient (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required in the elderly.

Paediatric population

Dosage

Children aged 1-18 years

Gastric antisecretory treatment when the oral route is not possible

Patients who cannot take oral medication may be treated parenterally once daily, as a part of a full treatment period for GERD (see doses in table 2 below).

Usually the intravenous treatment duration should be short and transfer to oral treatment should be made as soon as possible.

 

Table 2.

Recommended intravenous doses of esomeprazole

Age group	Treatment of erosive reflux esophagitis	Symptomatic treatment of GERD
1–11 years	Weight <20 kg: 10 mg once daily Weight ≥ 20 kg: 10 mg or 20 mg once daily	10 mg once daily
12–18 years	40 mg once daily	20 mg once daily

 

Method of Administration

Injection

40 mg dose

5 ml of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes.

20 mg dose

2.5 ml or half of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes. Any unused solution should be discarded.

10 mg dose

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. 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.

10 mg dose

A quarter 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.

 

Children.

The medicinal product is used in children over 1 year of age as an agent of antisecretory therapy in the case when oral administration of the drug is not possible.

 

Overdose.

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

 

Adverse reactions.

Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most commonly reported in clinical trials (and also from post-marketing use). In addition, the safety profile is similar for different formulations, treatment indications, age groups and patient populations. No dose-related adverse reactions have been identified.

The following adverse reactions have been reported during clinical trials and after the introduction of esomeprazole into general medical practice. The reactions are classified according to frequency: common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000), very rare (< 1/10000), not known (cannot be estimated from the available data).

 

Blood and lymphatic system disorders	Rare: leukopenia, thrombocytopenia Very rare: agranulocytosis, pancytopenia
Immune system disorders	Rare: hypersensitivity reactions, e.g. fever, angioedema and anaphylactic reaction/shock
Metabolic disorders	Uncommon: peripheral oedema Rare: hyponatraemia Not known: hypomagnesaemia (see section "Precautions for use"); severe hypomagnesaemia can correlate with hypocalcaemia. Hypomagnesaemia may also be associated with 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 disorders	Rare: bronchospasm
Gastrointestinal disorders	Common: abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign) 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	Common: administration site reactions* Uncommon: dermatitis, pruritus, rash, urticaria Rare: alopecia, photosensitivity Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) Not known: subacute cutaneous lupus erythematosus (see section "Precautions for use")
Musculoskeletal and connective tissue disorders	Uncommon: fracture of the hip, wrist or spine (see section "Precautions for use") Rare: arthralgia, myalgia Very rare: muscular weakness
Renal and urinary disorders	Very rare: interstitial nephritis (in some patients, renal failure has been reported concomitantly)
Reproductive system and breast disorders	Very rare: gynaecomastia
General disorders	Rare: malaise, increased sweating.

* Administration site reactions have mainly observed in a study with high-dose exposure over 3 days (72 hours). No vascular irritation has been reported with intravenous esomeprazole, but a slight reaction of tissue inflammation has been observed at the site of subcutaneous injection. The severity of tissue irritation was related to the concentration of the solution.

 

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

Paediatric population

The safety drug profile in children corresponds to the known esomeprazole safety profile in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Doctors and pharmacists should be informed of any adverse reactions.

 

Shelf life. 18 months.

Shelf life after reconstitution

Chemical and physical in-use stability has been demonstrated for 12 hours at 30 °C. From a microbiological point of view the product should be used immediately.

 

Storage conditions. Store in the original container at a temperature not exceeding 30 °С.

Keep out of reach of children.

 

Incompatibility.

Do not use any medicinal product to reconstitute the solution other than those listed in this section "Method of administration and dosage".

 

Packaging.

Packaging No.1. Lyophilisate for solution for injection and infusion in clear glass vial stoppered with bromobutyl rubber stopper and sealed with aluminium flip off seal. 1 vial in a cardboard packing.

 

Packaging No.10. Lyophilisate for solution for injection and infusion in clear glass vial stoppered with bromobutyl rubber stopper and sealed with aluminium flip off seal. 10 vials in a cardboard packing.

 

Terms of dispensing. On prescription.

 

Manufacturer.

Steril-Gene Life Sciences (P) Ltd.

 

Manufacturer’s registered address.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry 605110, India.

 

Applicant.

SCAN BIOTECH LTD, India.

 

Applicant’s registered address.

E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India.

 

Last update. 30.07.2020