Peprazom/Peprazom IV

Peprazom: Esomeprazole magnesium. Peprazom IV: Esomeprazole sodium.

Peprazom DR cap: Each 20- and 40-mg delayed-release capsule contains esomeprazole magnesium dihydrate equivalent to 20- and 40-mg, respectively.
Peprazom IV powd for inj: Each vial contains: Esomeprazole (as sodium) 40 mg.

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 oral dosing with esomeprazole 20 mg and 40 mg, the onset of effect occurs within 1 hr. After repeated administration with esomeprazole 20 mg once daily for 5 days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6-7 hrs after dosing on day 5.
After 5 days of oral dosing with esomeprazole 20 mg and 40 mg, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hrs in symptomatic gastroesophageal reflux disease (GERD) patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hrs, respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
Using area under the curve (AUC) as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
Peprazom IV: 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 acid inhibition: Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks and in 93% after 8 weeks.
One (1) week treatment with esomeprazole 20 mg twice daily and appropriate antibiotics, results in successful eradication of H. pylori in approximately 90% of patients.
After eradication treatment for 1 week, there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
In a randomized, double-blind, placebo-controlled clinical study, patients with endoscopically confirmed peptic ulcer bleeding characterized as forrest la, lb, lla or llb (9%, 43%, 38% and 10%, respectively) were randomized to receive esomeprazole solution for infusion (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either esomeprazole 80 mg as an IV infusion over 30 mins followed by a continuous infusion of 8 mg/hr or placebo for 72 hrs. After the initial 72-hr period, all patients received open-label esomeprazole 40 mg orally for 27 days for acid suppression. The occurrence of rebleeding within 3 days was 5.9% in the esomeprazole treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleeding in the esomeprazole treated versus the placebo-treated group 7.7% versus 13.6%.
Other effects related to acid inhibition: During treatment with antisecretory drugs, serum gastrin increases in response to the decreased acid secretion.
An increased number of Enterochromaffin-like (ECL) cells possibly related to the increased serum gastrin levels, has been observed in some patients during long-term treatment with esomeprazole.
During long-term treatment with antisecretory drugs, gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means including proton-pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton-pump inhibitors may lead to slightly increased risk of gastrointestinal infections eg, Salmonella and Campylobacter.
In 2 studies with ranitidine as an active comparator, esomeprazole showed better effect in healing of gastric ulcers in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) selective NSAIDs.
In 2 studies with placebo as comparator, esomeprazole showed better effect in the prevention of gastric and duodenal ulcers in patients using NSAIDs (aged >60 and/or with previous ulcer), including COX-2 selective NSAIDs.
Pharmacokinetics: Absorption and distribution: Peprazom: Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hrs after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once-daily administration. For esomeprazole 20 mg, the corresponding values are 50% and 68%, respectively. The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% plasma protein bound.
Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
Distribution: Peprazom IV: The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% plasma protein bound,
Metabolism and excretion: Esomeprazole is completely metabolised by the cytochrome P-450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 17 L/hr after a single dose and about 9 L/hr after repeated administration. The plasma elimination half-life (t_½) is about 1.3 hrs after repeated once-daily dosing. The pharmacokinetics of esomeprazole has been studied in doses up to 40 mg twice daily. The area under the plasma concentration-time curve (AUC) increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a more than dose proportional increase in AUC after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite.
Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.
The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Peprazom IV: Following repeated doses of 40 mg administered as intravenous injections, the mean peak plasma concentration is approx. 13.6 micromol/L. The mean peak plasma concentration after corresponding oral doses is approx. 4.6 micromol/L. A smaller increase (of approximately 30%) can be seen in total exposure after intravenous administration compared to oral administration. 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.
The major Metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Special patient populations: Approximately 2.9±1.5% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of esomeprazole 40 mg, the mean AUC was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations (C_max)were increased by about 60%.
These findings have no implications for the dosage of esomeprazole.
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Following a single dose of esomeprazole 40 mg, the mean AUC is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the dosage of esomeprazole.
Peprazom IV: 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 ring, 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 will) once-daily dosing.
No studies have been performed in patients with decreased renal function. Since the kidney Is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Impaired Organ Function: The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the AUC of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe dysfunction. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing. No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Pediatric: Peprazom: Adolescents 12-18 years: Following repeated-dose administration of esomeprazole 20 mg and 40 mg. the total exposure (AUC) and the time to reach maximum plasma drug concentration (t_max) in 12-18 years was similar to that in adults for both esomeprazole doses.
Peprazom IV: In a randomized, 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 to 18 years old of which 50 patients (7 children in the age group 1 to 5 years) completed the study and were evaluated for the pharmacokinelics of esomeprazole.
The table below describes the 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 Css, 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. (See Table 1.)

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Model based predictions Indicate that 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.
Chromogranin A (CgA) also increases due to decreased gastric acidity.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients during long term treatment with orally administered esomeprazole.
During long-term oral treatment with antisecretory drugs gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means Including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter in hospitalised patients, possibly also Clostridium difficile.
Paediatric population: 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 printery endpoint time to discontinuation due to symptom worsening.
In a placebo-controlled study (52 patients aged < 1 month) efficacy and safety in patients with symptoms of GERD were evaluated, Esomeprazole 0.5 mg/kg once daily was given 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 lime 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.
Toxicology: Preclinical Safety Data: Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and toxicity to reproduction. Carcinogenicity studies in the rat with the racemic mixture have shown gastric enterochromaffin-like (ECL)-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.

Peprazom: Symptomatic treatment of gastroesophageal reflux disease (GERD) and erosive reflux esophagitis.
Long-term management of patients with healed esophagitis to prevent relapse. In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori and healing associated with duodenal ulcer; prevention of relapse of peptic ulcers in patients with Helicobacter pylori-associated ulcers.
Patients requiring continued NSAID therapy; healing of gastric ulcers associated with NSAID therapy; prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.
Prolonged treatment after IV-induced prevention of rebleeding of peptic ulcers.
Treatment of Zollinger-Ellison syndrome.
Peprazom IV: Esomeprazole (Peprazom IV) 40 mg Powder for Solution for Injection is indicated for: Adults: Gastric antisecretory treatment when the oral route is not possible, such as: Gastroesophageal reflux disease (GERD) 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 patients at risk.
Prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.
Children and adolescents aged 1-18 years: Gastric antisecretory treatment when the oral route is not possible, such as: Gastroesophageal reflux disease in patients with erosive reflux esophagitis and/or severe symptoms of reflux.

Peprazom: Adults and Adolescents (12 years): Gastroesophageal Reflux Disease (GERD): Treatment of Erosive Reflux Esophagitis: 40 mg once daily for 4 weeks.
An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.
Long-Term Management of Patients with Healed Esophagitis to Prevent Relapse: 20 mg once daily.
Symptomatic Treatment of Gastroesophageal Reflux Disease (GERD): 20 mg once daily in patients without esophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily. In adults, an on-demand regimen taking 20 mg once daily, when needed, can be used. In NSAID treated patients at risk of developing gastric and duodenal ulcers, subsequent symptom control using an on-demand regimen is not recommended.
Adults: In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori and healing of Helicobacter pylori-associated duodenal ulcer, and prevention of relapse of peptic ulcers in patients with Helicobacter pylori-associated ulcers.
Esomeprazole 20 mg with amoxicillin 1 g and clarithromycin 500 mg, all twice daily for 7 days.
Patients Requiring Continued NSAID Therapy: Healing of Gastric Ulcers Associated with NSAID Therapy: Usual Dose: 20 mg once daily. The treatment duration is 4-8 weeks.
Prevention of Gastric and Duodenal Ulcers Associated with NSAID Therapy in Patients at Risk: 20 mg once daily.
Prolonged treatment after IV-induced prevention of rebleeding of peptic ulcers 40 mg once daily for 4 weeks after IV-induced prevention of rebleeding of peptic ulcers.
Treatment of Zollinger-Ellison Syndrome: Recommended Initial Dosage: 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. Based on the clinical data available, the majority of patients can be controlled on doses between 80-160 mg esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice daily.
Impaired Renal Function: Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution.
Impaired Hepatic Function: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of esomeprazole 20 mg should not be exceeded.
Elderly: Dose adjustment is not required in the elderly.
Peprazom IV: 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 esophagitis 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.
Prevention of rebieeding 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.
Impaired renal function: Dose adjustment is not required in patients with impaired renal function, Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution.
Impaired hepatic function: GERD: Dosage 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 riot be exceeded.
Bleeding ulcers: Dose adjustment is not required In patients with mild to moderate liver impairment. For patients with severe liver impairment, following an Initial bolus dose of 80 mg Esomeprazole 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.
Pediatric population (children and adolescent aged 1-18 years): Gastric antisecretory treatment when the oral route Is not possible: Patients who cannot lake oral medication may be treated parenterally once daily, as a part of a full treatment period for GERD (see doses in table as follows).
Usually the intravenous treatment duration should be short and transfer to oral treatment should be made as soon as possible.
Recommended intravenous doses of Esomeprazole: (See Table 2.)

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Administration: Peprazom: The capsules should be swallowed whole with liquid. The capsules should not be chewed or crushed.
For patients who have difficulty in swallowing, the capsules can be opened and their content dispersed in ½ a glass of non-carbonated water. No other liquids should be used as the enteric coating may be dissolved. Stir and drink the liquid with the granules immediately or within 30 mins. Rinse the glass with ½ a glass of water and drink. The granules must not be chewed or crushed.
For patients who cannot swallow, the content of the capsules can be dispersed in non-carbonated water and administered through a gastric tube. It is important that the appropriateness of the selected syringe and tube is carefully tested.
Through Gastric Tube: 1. Add the contents of a capsule into approximately 25 mL or 50 mL of water (for some tubes, dispersion in 50 mL water is needed to prevent the granules from clogging the tube). Stir.
2. Draw the suspension into a syringe and add approximately 5 mL of air.
3. Immediately shake the syringe for approximately 2 min to disperse the granules.
4. Hold the syringe with the tip up and check that the tip has not clogged.
5. Attach the syringe to the tube whilst maintaining the above position.
6. Shake the syringe and position it with the tip pointing down. Immediately inject 5-10 mL into the tube. Invert the syringe after injection and shake (the syringe must be held with the tip pointing up to avoid clogging of the tip).
7. Turn the syringe with the tip down and immediately inject another 5-10 mL into the tube. Repeat this procedure until the syringe is empty.
8. Fill the syringe with 25 mL of water and 5 mL of air and repeat step 6 if necessary to wash down any sediment left in the syringe. For some tubes, 50 mL water is needed.
Peprazom IV: Injection: 40 mg dose: 5 ml of the reconstituted solution (8mg/ml) should be given as intravenous injection over a period of at least 3 minutes,
20 mg dose: 2.5 ml or half of the reconstituted solution (8mg/ml) should be given as an intravenous injection over a period of approximately 3 minutes. Any unused solution should be discarded.
10 mg: 1.25 ml of the reconstituted solution (8mg/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.
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).

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

Hypersensitivity to the active substance esomeprazole or to other substituted benzimidazoles or to any of the excipients of this medicinal product.
Esomeprazole should not be used concomitantly with nelfinavir.
Use in children: Esomeprazole should not be used in children <12 years since no data is available.

In the presence of any alarm symptom (eg, significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with esomeprazole may alleviate symptoms and delay diagnosis.
Patients on long-term treatment (particularly those treated for >1 year) should be kept under regular surveillance.
Patients on on-demand treatment should be instructed to contact the physician if symptoms change in character. When prescribing esomeprazole for on demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered.
When prescribing esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4 eg, cisapride.
Peprazom contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Peprazom. It also contains parahydroxybenzoates, which may cause allergic reactions (possibly delayed).
Treatment with proton-pump inhibitors may lead to slightly increased risk of gastrointestinal infections eg, Salmonella and Campylobacter.
Co-administration of esomeprazole with atazanavir is not recommended. 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.
Peprazom IV: Hypomagnesemia: Severe hypomagnesemia has been reported in patients treated with PPIs like esomeprazole for at least 3 months, and in most cases for a year. Serious manifestations of hypomagnesemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesemia improved after magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
Risk of hip, wrist and spine fracture: Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
In healthy volunteers, concomitant 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 (te2) 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.
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
No in vivo interaction studies have been performed with the high dose iv regimen (80mg+80mg/h). The effect of esomeprazole on drugs metabolised by CYP2C19 may be inure pronounced during this regimen, and patients should be monitored closely for adverse effects, during the 3-day i.v. treatment period.
In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their Interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.
Unknown mechanism: When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration, a temporary withdrawal of esomeprazole may need to be considered.
Effects of other drugs on the pharmacokinetics of esomeprazole: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and a CYP3A4 inhibitor. clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP 3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC, 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.
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.
Effects on the Ability to Drive or Operate Machinery: No effects have been observed.

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

The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole administered orally or intravenously and post-marketing when administered orally. The reactions are classified according to frequency: common ≥1/100 to <1/10; uncommon ≥1/1,000 to <1/100; rare ≥1/10,000 to <1/1,000; very rare <1/10,000; 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.
Metabolism and nutrition disorders: Uncommon: Peripheral oedema. Rare: Hyponatraemia. Frequency not known: hypomagnesaemia.
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, diarrhoea, flatulence, nausea/vomiting. 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 end 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: Uncommon: Fracture of the hip, wrist or spine myalgia, 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 observed in a study with high-dose exposure over 3 days (72 hours).
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 cause relationship has been established.
Paediatric population: A randomised, open-label, multi-national study was conducted to evaluate the pharmacokinetics of repeated intravenous doses for days of once daily esomeprazole in paediatric patients 0 to 18 year old. A total of 57 patients (8 children in the age group 1-5 years) were included for safety evaluation. The safety results are consistent with the known safety profile of esomeprazole, and no new safety signal were identified.

Interaction studies have only been performed in adults: Effect of esomeprazole on the pharmacokinetics of other drugs: Medicinal products with pH-dependent absorption: The decreased intragastric acidity during treatment with esomeprazole, might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can decrease during treatment with esomeprazole.
Peprazom IV: 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 10 subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced.
Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP 2C19. 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 area under the curve (AUC), peak plasma concentration (C_max) and minimum plasma concentration (C_min)]. 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 daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg daily without omeprazole 20 mg daily. Co-administration of omeprazole (40 mg daily) reduced mean nelfinavir AUC, C_max and C_min by 36-39% and mean AUC, C_max and C_min for the pharmacologically active metabolite M8 was reduced by 75-92%. For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg daily). Treatment with omeprazole 20 mg daily had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg daily or everyday had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg daily or everyday had no effect on the exposure of lopinavir (with concomitant ritonavir). Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated.
Drugs metabolised by CYP2C19: Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with drugs metabolised by CYP2C19 eg, diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these drugs may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on-demand therapy. Concomitant administration of esomeprazole 30 mg resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of esomeprazole 40 mg resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUC_T by 15% and 41%, respectively.
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, post-marketing, a few isolated cases of elevated international normalised ratio (INR) of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.
In healthy volunteers, concomitant administration of esomeprazole 40 mg resulted in a 32% increase in AUC and a 31% prolongation of elimination half-life (t_½) but no significant increase in C_max of cisapride. The slightly prolonged QT_c interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole.
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin and quinidine.
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 Drugs on the Pharmacokinetics of Esomeprazole: Esomeprazole is metabolized by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily.), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC_T 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.
Peprazom IV: Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognized 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.
This medicine contains less than 1 mmol (23mg) of sodium per vial, so essentially "sodium-free".
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.
Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with drugs metabolized through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.
Interference with laboratory test: Increased CgA level may interfere with investigations for neuroendocrine tumors. To avoid this interference, esomeprazole treatment should be temporarily stopped for a least five days before CgA measurements.

Peprazom: Store at temperatures not exceeding 25°C. Protect from moisture.
Peprazom IV: Store below 30°C. Protect from light.
Shelf-Life: 24 months.

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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