Pompezo
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT POMPEZO (POMPEZO)
Composition:
Active substance: esomeprazole;
1 vial contains esomeprazole (as esomeprazole sodium) 40 mg;
Excipients: disodium edetate, sodium hydroxide.
Pharmaceutical form. Lyophilisate for solution for injection.
Main physicochemical properties: lyophilized white powder; prepared solution: clear colorless or slightly yellow solution.
Pharmacotherapeutic group.
Drugs used in acid-related disorders. Proton pump inhibitors. ATC code A02BC05.
Pharmacological Properties.
Pharmacodynamics.
Esomeprazole is the S-isomer of omeprazole, which reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the proton pump (PPI) in parietal cells. Both the R- and S-isomers of omeprazole exhibit similar pharmacodynamic activity.
Mechanism of Action
Esomeprazole is a weak base that accumulates and is converted into its active form in the highly acidic environment of the secretory canaliculi of parietal cells, where it inhibits the H+K+-ATPase enzyme—the proton pump—and suppresses both basal and stimulated acid secretion.
Pharmacodynamic Effects
After 5 days of oral administration at doses of 20 mg and 40 mg, esomeprazole maintained intragastric pH above 4 for an average of 13 hours and 17 hours, respectively, over a 24-hour period in patients with symptomatic gastroesophageal reflux disease (GERD). The effect is similar regardless of whether esomeprazole is administered orally or intravenously.
Using plasma drug concentration as an indirect parameter, such as the area under the plasma concentration-time curve (AUC), a correlation between acid secretion inhibition and AUC has been demonstrated after oral administration of esomeprazole.
In healthy volunteers receiving intravenous esomeprazole at a dose of 80 mg as a 30-minute bolus infusion followed by a continuous intravenous infusion at 8 mg/hour for 23.5 hours, intragastric pH remained above 4 and above 6 for an average of 21 hours and 11–13 hours, respectively, over a 24-hour period.
With oral administration of esomeprazole 40 mg, approximately 78% of patients with reflux esophagitis healed within 4 weeks, and 93% healed within 8 weeks of treatment.
In a randomized, double-blind, placebo-controlled clinical trial involving patients with endoscopically confirmed peptic ulcer bleeding classified as Forrest class Ia, Ib, IIa, or IIb (9%, 43%, 38%, and 10%, respectively), patients were randomized to receive either intravenous esomeprazole (n=375) or placebo (n=389). After endoscopic hemostasis, patients received either intravenous esomeprazole 80 mg as a 30-minute infusion followed by a continuous infusion at 8 mg/hour, or placebo, for 72 hours. After the initial 72-hour period, all patients were switched to oral esomeprazole 40 mg daily for 27 days to maintain acid suppression. The rate of recurrent bleeding within 3 days was 5.9% in the esomeprazole group versus 10.3% in the placebo group. At 30 days after therapy, the rates of recurrent bleeding were 7.7% and 13.6% in the esomeprazole and placebo groups, respectively.
During antisecretory therapy, plasma gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Available published data suggest that PPI therapy should be discontinued 5–14 days before measuring CgA levels. This allows CgA levels to return to normal ranges, as they may be falsely elevated during PPI treatment.
During long-term esomeprazole therapy in both children and adults, an increase in the number of enterochromaffin-like (ECL) cells has been observed, possibly due to elevated plasma gastrin levels. These findings are considered clinically insignificant.
With prolonged use of antisecretory agents, a slight increase in the incidence of gastric glandular cysts has been observed. Such changes are a physiological consequence of pronounced inhibition of gastric juice secretion; they are benign in nature and resolve after discontinuation of therapy.
Reduced gastric acidity from any cause, including PPI use, leads to increased bacterial load in the stomach, particularly organisms normally present in the gastrointestinal tract. PPI therapy may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, in hospitalized patients, and possibly also Clostridium difficile.
Children
In a placebo-controlled study (98 patients aged 1 to 11 months), the efficacy and safety of the drug were evaluated in patients with signs and symptoms of GERD. Esomeprazole at 1 mg/kg once daily was administered orally for 2 weeks (open-label phase), and 80 patients continued into an additional 4-week period (double-blind, treatment withdrawal phase). No significant difference was observed between esomeprazole and placebo regarding achievement of the primary endpoint or discontinuation due to symptom worsening.
In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of the drug were evaluated in patients with symptoms of GERD. Esomeprazole at 0.5 mg/kg once daily was administered orally for at least 10 days. No significant difference was observed between esomeprazole and placebo regarding the primary endpoint—the change in frequency of GERD symptoms compared to baseline.
Results from pediatric studies indicate that esomeprazole doses of 0.5 mg/kg and 1.0 mg/kg in infants aged <1 month and 1–11 months, respectively, reduce the mean percentage of time with intraesophageal pH < 4.0. The safety profile of the drug was similar to that observed in adults.
In a study involving pediatric patients with GERD (aged <1 to 17 years) receiving long-term proton pump inhibitor (PPI) therapy, 61% of children showed mild ECL cell hyperplasia, the clinical significance of which was unknown; no cases of atrophic gastritis or carcinoid tumors were observed.
Pharmacokinetics.
Distribution
The apparent volume of distribution at steady state in healthy volunteers is approximately 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins.
Metabolism
Esomeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of esomeprazole metabolism is dependent on the polymorphic CYP2C19, responsible for forming hydroxy- and desmethyl metabolites of esomeprazole. The remainder of metabolism is mediated by another specific isoenzyme, CYP3A4, which forms esomeprazole sulfone, the main metabolite in plasma.
Elimination
The parameters described below primarily reflect pharmacokinetics in individuals with functional CYP2C19 enzyme, i.e., pharmacokinetics in rapid metabolizers.
Total plasma clearance is approximately 17 L/hour after a single dose and about 9 L/hour after repeated administration. The elimination half-life (t½) of esomeprazole in plasma is approximately 1.3 hours with repeated once-daily dosing.
Esomeprazole is completely cleared from plasma between doses, and no tendency toward accumulation is observed with once-daily administration.
The main metabolites of esomeprazole do not affect gastric juice secretion. Approximately 80% of an oral dose is excreted in urine as metabolites, and the remainder in feces. Less than 1% of the parent compound is excreted in urine.
Linearity/Non-linearity
AUC increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear relationship between dose and AUC after repeated dosing. This time- and dose-dependent relationship is likely due to reduced presystemic metabolism and systemic clearance, possibly caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.
With repeated intravenous administration of esomeprazole 40 mg, the mean maximum plasma concentration (Cmax) is approximately 13.6 µmol/L. The mean Cmax after corresponding oral doses is approximately 4.6 µmol/L. A smaller increase (approximately 30%) in AUC is observed with intravenous administration compared to oral administration. A linear, dose-dependent increase in AUC was observed after 30-minute intravenous infusions of esomeprazole (40 mg, 80 mg, or 120 mg) followed by continuous infusion (at 4 mg/h or 8 mg/h) for 23.5 hours.
Special Patient Populations
Patients with CYP2C19 Polymorphism
Approximately 2.9 ± 1.5% of the population lacks functional CYP2C19 enzyme and are referred to as poor metabolizers. In these individuals, esomeprazole metabolism is likely catalyzed primarily by CYP3A4. After multiple doses of esomeprazole 40 mg once daily, the mean AUC was approximately 100% higher in poor metabolizers than in individuals with functional CYP2C19 (extensive metabolizers). The mean Cmax was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These data do not require dosage adjustments for esomeprazole.
Patients with Hepatic Impairment
Metabolism of esomeprazole may be impaired in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of esomeprazole AUC. Therefore, patients with GERD and severe hepatic impairment should not exceed the maximum dose of 20 mg. For patients with bleeding ulcers and severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion of esomeprazole at a maximum rate of 4 mg/hour for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not show a tendency to accumulate with once-daily administration.
Patients with Renal Impairment
Studies in patients with impaired renal function have not been conducted. Since the kidneys are responsible for excretion of esomeprazole metabolites but not the parent compound, significant changes in esomeprazole metabolism are not expected in patients with renal impairment.
Elderly Patients
Esomeprazole metabolism is only slightly altered in elderly patients (71–80 years of age).
Gender Differences
After a single 40 mg dose, the mean AUC in women is approximately 30% higher than in men. No gender-related differences are observed with repeated once-daily administration of esomeprazole. Similar differences were observed with intravenous administration. These data do not affect esomeprazole dosing.
Children
In a randomized, open-label, international multiple-dose study, esomeprazole was administered as a 3-minute injection once daily for 4 days. A total of 59 children aged 0 to 18 years were enrolled, of whom 50 (including 7 children aged 1 to 5 years) completed the study and were included in the pharmacokinetic evaluation.
Table 1 presents the systemic exposure results of esomeprazole after 3-minute intravenous injection in pediatric patients and healthy adult volunteers. Values in Table 1 are expressed as geometric means (range). The 20 mg dose in adults was administered as a 30-minute infusion. Maximum steady-state plasma concentration (Css,max) was assessed 5 minutes after dosing in all pediatric age groups, and in adult patients 7 minutes after the 40 mg dose and at the end of the 20 mg infusion.
| Age group |
Dose group |
AUC (μmol ×h/L) |
Css, 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 months* |
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) |
* The age group from 0 to 1 month included patients with corrected age (sum of gestational age and postnatal age in completed weeks) ≥ 32 completed weeks and < 44 completed weeks. The age group from 1 to 11 months included patients with corrected age ≥ 44 completed weeks.
** Two patients were excluded: one most likely due to reduced CYP2C19 isoenzyme activity, the other due to concomitant use of a CYP3A4 isoenzyme inhibitor.
According to the developed model, Css,max after intravenous administration of esomeprazole via 10-minute, 20-minute, and 30-minute infusions will decrease by 37–49%, 54–66%, and 61–72%, respectively, across all age groups and dosing groups compared to Css,max after a 3-minute injection.
Clinical characteristics.
Indications.
Adults
- Antisecretory therapy when oral administration is not feasible, for example:
- Gastroesophageal reflux disease (GERD) in patients with esophagitis and/or severe reflux symptoms;
- treatment of gastric ulcers associated with nonsteroidal anti-inflammatory drug (NSAID) therapy;
- prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.
- Prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcers.
Children aged 1 to 18 years
- Antisecretory therapy when oral administration is not feasible, for example:
- GERD in patients with erosive reflux esophagitis and/or severe reflux symptoms.
Contraindications.
- Hypersensitivity to the active substance, to other substituted benzimidazoles, or to any of the excipients of the medicinal product.
- Concomitant use with atazanavir or nelfinavir (see section "Interaction with other medicinal products and other forms of interaction").
Interaction with other medicinal products and other forms of interaction.
Interaction studies have been conducted only in adults.
Effect of esomeprazole on the pharmacokinetics of other drugs
Protease inhibitors
Interactions between omeprazole and certain protease inhibitors have been reported. The clinical significance and mechanisms of these interactions are not always known. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other interaction mechanisms may occur via inhibition of CYP2C19.
Decreased plasma levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole; therefore, co-administration of these agents is not recommended.
Concomitant administration of omeprazole (40 mg once daily) with atazanavir (300 mg/ritonavir 100 mg) in healthy volunteers resulted in a significant reduction in atazanavir exposure (approximately 75 % reduction in AUC, Cmax, and minimum plasma concentration [Cmin]). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure.
Concomitant administration of omeprazole (20 mg daily) with atazanavir (400 mg/ritonavir 100 mg) in healthy volunteers reduced atazanavir AUC by approximately 30 % compared to atazanavir (300 mg/ritonavir 100 mg daily) administered without omeprazole (20 mg daily).
Concomitant administration of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin of nelfinavir by 36–39 %, and mean AUC, Cmax, and Cmin of its pharmacologically active metabolite M8 by 75–92 %.
Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended (see section "Special precautions for use"). Concomitant use of esomeprazole and nelfinavir is contraindicated (see section "Contraindications").
Increased plasma levels (80–100 %) of saquinavir (in combination with ritonavir) have been observed with concomitant use of omeprazole (40 mg daily).
Omeprazole (20 mg daily) had no effect on the AUC of darunavir (in combination with ritonavir) or amprenavir (in combination with ritonavir).
Esomeprazole (20 mg daily) had no effect on the AUC of amprenavir (with or without ritonavir).
Omeprazole (40 mg daily) did not alter the AUC of lopinavir (in combination with ritonavir).
Methotrexate
Elevated plasma methotrexate levels have been observed in some patients receiving concomitant proton pump inhibitors (PPIs). When high-dose methotrexate is administered, temporary discontinuation of esomeprazole should be considered.
Tacrolimus
Increased plasma levels of tacrolimus have been reported with concomitant use of esomeprazole. Enhanced monitoring of plasma tacrolimus levels and renal function (creatinine clearance) is recommended during concomitant use, and dose adjustment of tacrolimus may be necessary.
Drugs whose absorption is pH-dependent
Suppression of gastric acid secretion during treatment with esomeprazole and other PPIs may decrease or increase the absorption of drugs whose absorption is pH-dependent. As with other agents that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, whereas absorption of drugs such as digoxin may be increased during esomeprazole therapy. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10 % (up to 30 % in 2 out of 10 subjects). Rare cases of digoxin toxicity have been reported. However, caution should be exercised when high-dose esomeprazole is administered to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.
Drugs metabolized by CYP2C19
Esomeprazole inhibits CYP2C19, the primary enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, or phenytoin, plasma concentrations of these drugs may increase, and dose reduction may be required. In vivo interaction studies using intravenous formulations at high doses (80 mg + 8 mg/hour) have not been conducted. The effect of esomeprazole on drugs metabolized by CYP2C19 during such treatment regimens may be more pronounced, and patients should be closely monitored for adverse effects during the three-day intravenous esomeprazole infusion period.
Diazepam
Concomitant oral administration of esomeprazole (30 mg) resulted in a 45 % reduction in the clearance of diazepam, a CYP2C19 substrate.
Phenytoin
Concomitant oral administration of esomeprazole (40 mg) in patients with epilepsy resulted in a 13 % increase in phenytoin plasma Cmin. Monitoring of plasma phenytoin levels is recommended at the beginning and after completion of esomeprazole therapy.
Voriconazole
Administration of omeprazole (40 mg once daily) increased Cmax and AUC of voriconazole (a CYP2C19 substrate) by 15 % and 41 %, respectively.
Cilostazol
Omeprazole and esomeprazole act as inhibitors of CYP2C19. In a crossover study, administration of omeprazole (40 mg) to healthy volunteers increased Cmax and AUC of cilostazol by 18 % and 26 %, respectively, and of one of its active metabolites by 29 % and 69 %, respectively.
- Cisapride*
In healthy volunteers, concomitant oral administration with esomeprazole (40 mg) increased AUC by 32 % and prolonged t½ by 31 %, but no significant increase in Cmax of cisapride was observed. The slight QTc interval prolongation observed with cisapride monotherapy was not observed during concomitant administration of cisapride and esomeprazole.
Warfarin
A clinical study showed that co-administration of oral esomeprazole 40 mg in patients on warfarin therapy maintained coagulation time within acceptable limits. However, during post-marketing surveillance, several isolated cases of clinically significant increases in the international normalized ratio (INR) have been reported during concomitant oral administration of these agents. Monitoring is recommended at the start and after discontinuation of concomitant esomeprazole use in patients receiving warfarin or other coumarin derivatives.
Clopidogrel
Pharmacokinetic (PK)/pharmacodynamic (PD) interaction studies between clopidogrel (loading dose 300 mg/maintenance dose 75 mg daily) and esomeprazole (40 mg daily orally) in healthy volunteers showed a 40 % average reduction in AUC of the active metabolite of clopidogrel and a 14 % average reduction in maximum platelet aggregation inhibition (ADP-induced).
In a study in healthy volunteers receiving clopidogrel together with esomeprazole and acetylsalicylic acid (ASA) in fixed-dose combination (20 mg + 81 mg, respectively), compared to clopidogrel monotherapy, a nearly 40 % reduction in AUC of clopidogrel's active metabolite was observed. However, maximum levels of platelet aggregation inhibition (ADP-induced) were similar between the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA.
Observational and clinical studies have yielded conflicting data regarding the clinical implications of the PK/PD interaction between esomeprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.
Effect of other medicinal products on the pharmacokinetics of esomeprazole
Drugs that inhibit CYP2C19 and/or CYP3A4 activity
Esomeprazole is metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubles the AUC of esomeprazole. Concomitant administration of esomeprazole with a combined inhibitor of CYP2C19 and CYP3A4 may increase esomeprazole AUC by more than two-fold. The CYP2C19 and CYP3A4 inhibitor voriconazole increased the AUCτ of omeprazole by 280 %. Dose adjustment of esomeprazole is usually not required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and in cases requiring long-term treatment.
Drugs that induce CYP2C19 and/or CYP3A4 activity
Agents known to induce CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), may reduce esomeprazole plasma levels by accelerating its metabolism.
Medicinal products investigated without clinically significant interaction
Amoxicillin and quinidine
Esomeprazole was found not to have clinically significant effects on the pharmacokinetics of amoxicillin or quinidine.
Naproxen or rofecoxib
No pharmacokinetic interaction was observed during short-term studies of concomitant administration of esomeprazole with naproxen or rofecoxib.
Special precautions for use
In the presence of any alarming symptoms (such as significant, unexplained weight loss, recurrent vomiting, dysphagia, hematemesis, or melena) or suspicion of, or confirmed diagnosis of gastric ulcer, malignancy should be ruled out, since esomeprazole may mask symptoms and delay diagnosis.
Gastrointestinal infections
Use of PPIs may slightly increase the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").
Vitamin B12 absorption
Esomeprazole, like all agents that inhibit acid secretion, may impair absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low vitamin B12 stores or risk factors for impaired vitamin B12 absorption during long-term therapy.
Hypomagnesemia
Cases of severe hypomagnesemia have been reported in patients treated with PPIs such as esomeprazole for at least three months, and in most cases, for a year or longer. Hypomagnesemia may present with serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, and its onset may be insidious and remain unrecognized. In most patients with hypomagnesemia, the condition improved after magnesium supplementation and discontinuation of PPI therapy. For patients requiring prolonged treatment or those taking PPIs concomitantly with digoxin or other agents that may cause hypomagnesemia (e.g., diuretics), it may be appropriate to measure magnesium levels before initiating PPI therapy and periodically during treatment.
Fracture risk
PPIs, particularly when used at high doses and for prolonged periods (>1 year), may slightly increase the risk of hip, wrist, and spine fractures, primarily in elderly patients or those with other risk factors. Observational studies suggest that PPIs may increase the overall fracture risk by 10–40%. This increased risk may be partly attributable to other risk factors. Patients at risk of osteoporosis should be managed according to current clinical guidelines and should receive adequate intake of vitamin D and calcium.
Subacute cutaneous lupus erythematosus (SCLE)
PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, patients should seek immediate medical advice, and discontinuation of the drug should be considered. A history of subacute cutaneous lupus erythematosus during previous PPI therapy may increase the risk of recurrence with other PPIs.
Concomitant use with other medicinal products
Concomitant use of esomeprazole with atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If co-administration of atazanavir with a PPI is considered necessary, careful patient monitoring is recommended, and the atazanavir dose should be increased to 400 mg in combination with 100 mg ritonavir; the esomeprazole dose should not exceed 20 mg.
Esomeprazole is an inhibitor of CYP2C19. Potential interactions with drugs metabolized by CYP2C19 should be considered at the start and end of esomeprazole therapy. An interaction between clopidogrel and omeprazole has been reported (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction is not fully established. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.
Severe cutaneous adverse reactions (SCARs)
Very rare cases of severe cutaneous adverse reactions (SCARs), including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), some of which may be life-threatening or fatal, have been reported with esomeprazole treatment.
Patients should be informed about the possible signs and symptoms of severe cutaneous adverse reactions (EM/SJS/TEN/DRESS) and should seek immediate medical advice if any characteristic signs or symptoms occur.
If signs or symptoms of severe skin reactions occur, esomeprazole should be discontinued immediately and additional medical care / close patient monitoring should be provided.
Re-administration of the drug should not be attempted in patients who have experienced EM/SJS/TEN/DRESS.
Effect on laboratory test results
Elevated chromogranin A (CgA) levels may interfere with investigations for neuroendocrine tumors. To avoid this interference, treatment with the medicinal product should be temporarily discontinued at least 5 days before CgA assessment (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI therapy.
Each vial of the medicinal product Pompex contains less than 1 mmol sodium (23 mg) per 40 mg, and therefore is considered essentially "sodium-free".
Use during pregnancy or breastfeeding
Pregnancy
There are currently insufficient data on the use of esomeprazole during pregnancy. A somewhat larger amount of epidemiological data on the use of racemic omeprazole during pregnancy indicates no congenital malformations or fetotoxic effects. Animal studies with esomeprazole have not shown any direct or indirect adverse effects on embryonal/fetal development. Studies in animals with the racemic mixture have not shown any direct or indirect effects on pregnancy, delivery, or postnatal development. The medicinal product should be used with caution during pregnancy.
A moderate amount of data from pregnant women (from 300 to 1000 pregnancy cases) indicates no malformative or toxic effects of esomeprazole on the fetus or the health of the newborn child.
Animal studies indicate no direct or indirect adverse effect of esomeprazole on reproductive performance due to its toxic effects.
Breastfeeding
It is unknown whether esomeprazole passes into human breast milk. There is insufficient information on the consequences of esomeprazole exposure in newborns/infants. In view of this, the medicinal product should not be used during breastfeeding.
Fertility
Animal studies with racemic omeprazole indicate no effect of omeprazole on fertility following oral administration.
Ability to affect reaction speed when driving or operating machinery
Esomeprazole has minimal effect on the ability to drive or operate machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported (see section "Adverse reactions"). If such disturbances occur, patients should refrain from driving or operating machinery.
Dosage and Administration
Adults.
Dosage.
Antisecretory therapy when oral administration of esomeprazole is not feasible
For patients who cannot take esomeprazole orally, the drug may be administered parenterally at a dose of 20–40 mg once daily.
For patients with reflux esophagitis, the recommended dose is 40 mg once daily.
For patients receiving symptomatic treatment of gastroesophageal reflux disease, the dose is 20 mg once daily.
For treatment 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 in high-risk patients, the dose is 20 mg once daily.
Treatment with intravenous esomeprazole is generally short-term; patients should be switched to oral therapy as soon as possible.
Prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcer
After endoscopic therapy of acute bleeding from gastric or duodenal ulcer, administer 80 mg of the drug as an intravenous bolus infusion over 30 minutes, followed by continuous intravenous infusion of the drug at a rate of 8 mg/hour for 3 days (72 hours).
After parenteral treatment, therapy should be continued with oral acid-suppressing agents.
Administration method.
Instructions for preparation of the reconstituted solution are provided below in this section (see "Instructions for use, handling, and disposal (where applicable)").
Injections.
Dose of 40 mg:
Administer 5 mL of reconstituted solution (8 mg/mL) as an intravenous injection over at least 3 minutes.
Dose of 20 mg:
Administer 2.5 mL or half of the reconstituted solution (8 mg/mL) as an intravenous injection over at least 3 minutes. Discard any unused solution.
Infusions.
Dose of 40 mg:
Administer the reconstituted solution as an intravenous infusion over 10–30 minutes.
Dose of 20 mg:
Administer half of the reconstituted solution as an intravenous infusion over 10–30 minutes. Discard any unused solution.
Dose of 80 mg:
Administer the reconstituted solution as a prolonged intravenous infusion over 30 minutes.
Dose of 8 mg/hour:
Administer the reconstituted solution as a prolonged intravenous infusion over 71.5 hours (calculated infusion rate: 8 mg/hour; shelf life of the reconstituted solution is specified in the section "Shelf life").
Special patient groups
Patients with renal impairment
No dose adjustment is required for patients with renal impairment. Since experience with esomeprazole in patients with severe renal impairment is limited, the drug should be used with caution in these patients (see section "Pharmacokinetics").
Patients with hepatic impairment
GERD: No dose adjustment is required for patients with mild to moderate hepatic impairment. The maximum dose should not exceed 20 mg in patients with severe hepatic impairment (see section "Pharmacokinetics").
Bleeding ulcers: No dose adjustment is required for patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, after an initial bolus dose of 80 mg, continued administration as a prolonged intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section "Pharmacokinetics").
Elderly patients
No dose adjustment is required.
Children aged 1 to 18 years
Dosage.
As an agent for inhibition of gastric secretion when oral administration of esomeprazole is not feasible
For patients who cannot take the drug orally, the drug may be administered parenterally once daily during the full course of treatment of GERD (doses are specified in the table below).
Treatment with intravenous esomeprazole should generally be brief; patients should be switched to oral esomeprazole as soon as possible.
Recommended doses of esomeprazole for intravenous administration
| Age group |
Treatment of erosive reflux esophagitis |
Symptomatic treatment of GERD |
| 1-11 years |
Body weight <20 kg: 10 mg once daily |
10 mg once daily |
| 12-18 years |
40 mg once daily |
20 mg once daily |
Method of administration.
Instructions for preparing the reconstituted solution are provided in the section below («Instructions for use, handling, and disposal (where applicable)»).
Injections.
40 mg dose:
Administer 5 ml of reconstituted solution (8 mg/ml) as an intravenous injection over not less than 3 minutes.
20 mg dose:
Administer 2.5 ml or half of the reconstituted solution (8 mg/ml) as an intravenous injection over not less than 3 minutes. Discard any unused solution.
10 mg dose:
Administer 1.25 ml of reconstituted solution (8 mg/ml) as an intravenous injection over not less than 3 minutes. Discard any unused solution.
Infusions.
40 mg dose:
Administer the reconstituted solution as an intravenous infusion over 10–30 minutes.
20 mg dose:
Administer half of the reconstituted solution as an intravenous infusion over 10–30 minutes. Discard any unused solution.
10 mg dose:
Administer a quarter of the reconstituted solution as an intravenous infusion over 10–30 minutes. Discard any unused solution.
Instructions for use, handling, and disposal (where applicable).
Before administration, visually inspect the reconstituted solution for particles and discoloration. Use only clear solution. The solution is intended for single use only.
If the entire reconstituted content of the vial is not required, any unused solution must be discarded according to local requirements.
Injection solution 40 mg.
Prepare the injection solution (8 mg/ml) by adding 5 ml of 0.9% sodium chloride for intravenous use to a 40 mg esomeprazole vial.
The reconstituted injection solution is clear and colourless or slightly yellow.
Infusion solution 40 mg.
Prepare the infusion solution by dissolving the contents of one 40 mg esomeprazole vial in 100 ml of 0.9% sodium chloride for intravenous use.
Infusion solution 80 mg.
Prepare the infusion solution by dissolving the contents of two 40 mg esomeprazole vials in 100 ml of 0.9% sodium chloride for intravenous use.
The reconstituted infusion solution is clear and colourless or slightly yellow.
Children.
The medicinal product may be used in children aged 1 year and older as an antisecretory agent when oral administration of esomeprazole is not feasible.
Overdose.
Data regarding intentional overdose are very limited. Symptoms described following ingestion of 280 mg of esomeprazole included gastrointestinal symptoms and weakness. A single oral dose of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours did not result in any adverse effects. There is no specific antidote. Esomeprazole is highly bound to plasma proteins, so elimination via dialysis is minimal. In case of overdose, symptomatic and supportive treatment should be administered.
Adverse Reactions
Among the adverse reactions most commonly observed in clinical trials and during the post-marketing period of esomeprazole use, headache, abdominal pain, diarrhea, and nausea are reported. Furthermore, the safety profile of esomeprazole is consistent across different dosage forms, indications, age groups, and patient populations. Dose-dependent adverse reactions have not been identified.
The adverse reactions listed below have been reported or suspected during clinical studies with oral or intravenous administration of esomeprazole, as well as during the post-marketing period with oral administration. Reactions are categorized according to their frequency: very common (> 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).
Blood and lymphatic system disorders:
Rare – leukopenia, thrombocytopenia; very rare – agranulocytosis, pancytopenia.
Immune system disorders:
Rare – hypersensitivity reactions, e.g., fever, angioedema, and anaphylactic reaction/shock.
Metabolism and nutrition disorders:
Uncommon – peripheral edema; rare – hyponatremia; frequency not known – hypomagnesemia (see section "Special Warnings and Precautions for Use"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
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, fundic gland polyps (benign); uncommon – dry mouth; rare – stomatitis, gastrointestinal candidiasis; frequency 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 – injection site reactions*; uncommon – dermatitis, pruritus, rash, urticaria; rare – alopecia, photosensitivity; very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS); frequency not known – subacute cutaneous lupus erythematosus (see section "Special Warnings and Precautions for Use").
Musculoskeletal and connective tissue disorders:
Uncommon – fracture of hip, wrist, or spine (see section "Special Warnings and Precautions for Use"); rare – arthralgia, myalgia; very rare – muscle weakness.
Renal and urinary disorders:
Very rare – interstitial nephritis; in some patients, renal failure has also been observed concurrently.
Reproductive system and breast disorders:
Very rare – gynecomastia.
General disorders and administration site conditions:
Rare – malaise, increased sweating.
*Injection site reactions were primarily observed in a study using high-dose esomeprazole administered over 3 days (72 hours).
Irreversible visual disturbances have been reported in isolated cases in critically ill patients receiving intravenous omeprazole (racemate), particularly at high doses; however, a causal relationship has not been established.
Paediatric population
A randomized, open-label international study was conducted to evaluate the pharmacokinetics of multiple-dose intravenous esomeprazole administered over 4 days once daily in children aged 0 to 18 years (see section "Pharmacokinetics"). A total of 57 patients (including 8 children aged 1–5 years) were included in the safety assessment. The safety data for the medicinal product were consistent with the known safety profile of esomeprazole, and no new patient safety concerns were identified.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.
Packaging.
40 mg in a vial; 1 vial in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Mefar Ilac San. A.Ş. /
Mefar Ilac San. A.S.
Manufacturer's address and place of business.
Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.
Marketing Authorization Holder.
WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.