Esoferr

Esomeprazole.

DR cap: ESOFERR 20: Each delayed-release capsule contains: Esomeprazole magnesium trihydrate equivalent to esomeprazole 20 mg.
ESOFERR 40: Each delayed-release capsule contains: Esomeprazole magnesium trihydrate equivalent to esomeprazole 40 mg.
Powd for inj: Each vial contains: Esomeprazole sodium 42.5 mg equivalent to Esomeprazole 40 mg.

Pharmacology: Pharmacodynamics: Esomeprazole, a proton pump inhibitor, is the S-isomer of omeprazole. 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. Esomeprazole blocks the final step in acid production, resulting in potent, long-lasting inhibition of gastric acid secretion.
Pharmacokinetics: DR cap: The area under the plasma concentration-time curve from time zero to the last observed quantifiable concentration (AUC_0-t), area under the plasma concentration-time curve from time zero to infinity (AUC_0-inf), the peak plasma concentration of the drug (C_max), time needed to achieve the peak plasma concentration (t_max) and the elimination hal-life (t_1/2) of esomeprazole were defined as the main parameters in the bioequivalence study of ESOFERR 40 mg.
The arithmetic means AUC_0-t, AUC_0-inf, C_max and t_1/2 for the test drug T₁ were 4497.55 (2624.01) ng·hour/ml, 4815.51 (2612.49) ng·hour/ml, 1929.08 (801.82) ng/ml, and 1.29 (0.47) hours, respectively, with the median (range) t_max of 2.00 (1.00-4.00) hours. The arithmetic means AUC_0-t, AUC_0-inf, C_max and t_1/2 for the test drug T₂ were 4635.49 (2952.30) ng·hour/ml, 4976.08 (2961.25) ng·hour/ml, 1789.35 (792.10) ng/ml, and 1.25 (0.47) hours, respectively, with the median (range) t_max of 2.25 (1.25-5.00) hours. The arithmetic means AUC_0-t, AUC_0-inf, C_max and t_1/2 for the comparator product R₁ were 4376.89 (2645.21) ng·hour/ml, 4698.43 (2625.27) ng·hour/ml, 1824.12 (763.69) ng/ml, and 1.29 (0.44) hours, respectively, with the median (range) t_max of 2.13 (0.75-5.00) hours. The arithmetic means AUC_0-t, AUC_0-inf, C_max and t_1/2 for the comparator product R₂ were 4329.59 (2765.75) ng·hour/ml, 4626.35 (2827.19) ng·hour/ml, 1808.73 (784.53) ng/ml, and 1.20 (0.52) hours, respectively, with the median (range) t_max of 2.25 (1.25-6.00) hour.
The geometric mean ratios (90% confidence intervals) of the test drug/comparator product for esomeprazole were 102.99% (94.13-112.68%) for AUC_0-t and 101.32% (91.91-111.70%) for C_max. The t_max and t_1/2 values of test drug and comparator product for esomeprazole were found not significantly different.
The bioequivalence of the two products was concluded based on the 90% confidence interval of the test/comparator-geometric means ratio within the range of 80.00 to 125.00% for both AUC_0-t and C_max.
Hence, it was concluded that ESOFERR 40 mg was bioequivalent to the comparator drug.
Powd for inj: Distribution: The apparent volume of distribution at steady state in healthy subject is approximately 16 L. Esomeprazole is 97% plasma protein bound.
Metabolism and excretion: Esomeprazole is completely metabolized by the cytochrome P450 (CYP) isoenzyme CYP2C19 and the remainder is metabolized by the cytochrome P450 (CYP) isoenzyme CYP3A4. The major metabolites of esomeprazole have no effect on gastric acid secretion. The plasma elimination half-life is about 1.3 hours.
Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration.

DR cap: Esomeprazole delayed-release capsule is indicated for: Gastroesophageal Reflux Disease (GERD): treatment of erosive reflux esophagitis.
Long-term management of patients with healed esophagitis to prevent relapse.
Symptomatic treatment of gastroesophageal reflux disease (GERD).
In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori: healing of Helicobacter pylori associated duodenal ulcer.
Patients requiring continued NSAID therapy: healing of gastric ulcers associated with NSAID therapy.
Prevention of gastric and duodenal ulcers associated with continuous NSAID therapy in patient at risk. Patients are considered to be at risk due to their age (>60 years) and documented history of peptic ulcer. Available clinical controlled study do not extend beyond 6 months.
Treatment of Zollinger-Ellison syndrome.
Powd for inj: Esomeprazole injection is indicated for: Gastric antisecretory treatment when the oral route is not possible, such as: Gastro esophageal reflux disease in patients with esophagitis and/or severe symptoms of reflux.
Healing of gastric ulcers associated with NSAIDs therapy.
The short term maintenance of hemostasis and prevention of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.

DR cap: The capsules should be swallowed whole with liquid. The capsules should not be chewed or crushed. For patients who have difficulty in swallowing, the contents of a capsule can also be mixed in half a glass of noncarbonated water. No other liquids should be used as the enteric coating pellets may be dissolved. Stir the content of the capsules inside the glass filled with noncarbonated water. Drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.
For patients who cannot swallow, the contents of a capsule can be mixed 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.
For preparation and administration instructions see Instructions for use and handling under Cautions for Usage.
Adults: Gastroesophageal Reflux Disease (GERD): Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks. An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms. Esomeprazole 40 mg should only be administered for patients with mucosal break of grade C and D under the LA classification system, the grade of which should be confirmed by endoscopic or radiological diagnosis. Patients who have GERD with erosive esophagitis of Grade A and B are recommended to be treated with esomeprazole 20 mg.
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 four 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.
In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori: Healing of Helicobacter pylori associated duodenal ulcer: 20 mg esomeprazole with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.
Patients requiring continued NSAID therapy: Healing of gastric ulcers associated with NSAID therapy: The usual dose is 20 mg once daily. The treatment duration is 4-8 weeks.
Prevention of gastric and duodenal ulcers associated with NSAID therapy in patient at risk: 20 mg once daily.
Treatment of Zollinger-Ellison syndrome: The recommended initial dosage is esomeprazole 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. The majority of patients can be controlled on doses between 80 to 160 mg esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice daily.
Children 12-18 years: Gastroesophageal Reflux Disease (GERD): Symptomatic treatment of gastroesophageal reflux disease (GERD): 20 mg once daily in patients without esophagitis. If symptom control has not been achieved after four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily, under medical supervision.
Children below the age of 12 years: Esomeprazole should not be used in children younger than 12 years since no data is available.
Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution (see Pharmacology: Pharmacokinetics under Actions).
Impaired hepatic function: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg esomeprazole should not be exceeded (see Pharmacology: Pharmacokinetics under Actions).
Elderly: Dose adjustment is not required in the elderly.
Powd for inj: Gastric antisecretory treatment when the oral route is not possible.
Patients who cannot take oral medicines may be treated parenterally with 20-40 mg once daily. Patients with reflux esophagitis should be treated with 40 mg once daily. Patients with 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.
Usually the IV treatment durations short and transfer to oral treatment should be made as soon as possible.
Maintenance of hemostasis 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 continuous intravenous infusion of 8 mg/hour given over 3 days (72 hours).
The parenteral treatment period should be followed by acid-suppression therapy with esomeprazole 40 mg gastro-resistant tablet once daily for 4 weeks.
Children and adolescent: Esomeprazole IV should not be used in children and adolescent since no data is available.
Impaired hepatic function: Treatment for bleeding ulcer patients with severe liver impairment, following an initial bolus dose of 80 mg esomeprazole for infusion, a continuous intravenous infusion dose of 4 mg/hour for 71.5 hours may be sufficient.
Method of administration: Injection: 40 mg dose: The reconstituted solution should be given as an intravenous injection over a period of at least 3 minutes.
20 mg dose: Half of the reconstituted solution should be given as an intravenous injection over a period of approximately 3 minutes. Any unused solution should be discarded.
Infusion: 40 mg dose: The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.
20 mg dose: Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded.
80 mg bolus dose: The reconstituted solution should be given as a continuous intravenous infusion over 30 minutes.
8 mg/hour 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/hour).

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.
DR cap: No specific antidote is known.

Hypersensitivity to esomeprazole, substituted benzimidazoles or any of the excipients of this medicinal product.
Esomeprazole should not be administered with atazanavir and nelfinavir (see Interactions).

In the presence of any alarm symptom (e.g., 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.
DR cap: Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing esomeprazole for on-demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered (see Interactions).
When prescribing esomeprazole 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 metabolized via CYP3A4 such as cisapride.
Some published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with a small increased risk for osteoporosis related fractures. However, in other similar observational studies no such increased risk was found.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Pregnancy and lactation.
Caution should be exercised when prescribing to pregnant women.
It is not known whether esomeprazole is excreted in human breast milk. Therefore esomeprazole should not be used during breast-feeding.
Powd for inj: Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as 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.
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.
Esomeprazole should be used during pregnancy only if clearly needed.
Because esomeprazole is likely to be excreted in human milk, women should discontinued breast-feeding.

The reactions are classified according to frequency: very common ≥10; 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 edema.
Rare: hyponatremia.
Very rare: hypomagnesemia: DR cap: severe hypomagnesemia may result in hypocalcemia. Hypomagnesemia may also result in hypokalemia.
Psychiatric disorders: Uncommon: insomnia.
Rare: agitation, confusion, depression.
Very rare: aggression, hallucinations.
Nervous system disorders: Common: headache.
Uncommon: dizziness, paresthesia, somnolence.
Rare: taste disturbance.
Eye disorders: DR cap: Rare: blurred vision.
Powd for inj: Uncommon: blurred vision.
Ear and labyrinth disorders: Uncommon: vertigo.
Respiratory, thoracic and mediastinal disorders: Rare: bronchospasm.
Gastrointestinal disorders: Common: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting.
Uncommon: dry mouth.
Rare: stomatitis, gastrointestinal candidiasis.
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: Powd for inj: administration site reactions.
Uncommon: dermatitis, pruritus, rash, urticaria.
Rare: alopecia, photosensitivity.
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).
Musculoskeletal, connective tissue and bone disorders: Rare: arthralgia, myalgia.
Very rare: muscular weakness.
Renal and urinary disorders: Very rare: interstitial nephritis.
Reproductive system and breast disorders: Very rare: gynecomastia.
General disorders and administration site conditions: Rare: malaise, increased sweating.

The absorption of ketoconazole and itraconazole can decrease during treatment with esomeprazole.
When esomeprazole is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these drugs may be increased and a dose reduction could be needed. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment with warfarin or other coumarin derivatives.
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
DR cap: The gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of drugs with gastric pH dependent absorption.
The absorption of erlotinib can decrease during treatment with esomeprazole.
The absorption of digoxin can increase during treatment with esomeprazole.
Concomitant administration of 40 mg esomeprazole and cisapride, resulted increase in area under the plasma concentration-time curve (AUC) and prolongation of elimination half-life (t_1/2) but no significant increase in peak plasma levels of cisapride.
Omeprazole has been reported to interact with some antiretroviral drugs. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. For some antiretroviral drug, such as atazanavir and nelfinavir, decreased serum level has been reported when given together with omeprazole. Due to similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, esomeprazole should not be coadministered with atazanavir and nelfinavir.
Concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions.
Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d), resulted in a doubling of the exposure (AUC) to esomeprazole.
Drug known induce CYP2C19 or CYP3A4, or both (such rifampicin and St. John's wort) may lead to decrease esomeprazole serum level and increasing the esomeprazole metabolism.
Powd for inj: Concomitant administration with esomeprazole and atazanavir is not recommended.
Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure.

Instructions for use and handling: DR cap: Administration through gastric tube: 1. Put the contents of a capsule into an appropriate syringe and fill the syringe with approximately 25 ml water and approximately 5 ml air. For some tubes, dispersion in 50 ml water is needed to prevent the pellets from clogging the tube.
2. Immediately shake the syringe for approximately 2 minutes to disperse the contents of a capsule.
3. Hold the syringe with the tip up and check that the tip has not clogged.
4. Attach the syringe to the tube whilst maintaining the above position.
5. 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).
6. 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.
7. Fill the syringe with 25 ml of water and 5 ml of air and repeat step 5 if necessary to wash down any sediment left in the syringe. For some tubes, 50 ml water is needed.
Powd for inj: Injection: A solution for injection is prepared by adding 5 ml of 0.9% sodium chloride for intravenous use to the vial with esomeprazole. The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Only clear solution should be used.
Infusion: A solution for infusion is prepared by dissolving the content of one vial with esomeprazole in up to 100 ml of 0.9% sodium chloride for intravenous use.
Infusion 80 mg: A solution for infusion is prepared by dissolving the content of two vials with esomeprazole 40 mg in up to 100 ml or 0.9% sodium chloride for intravenous use. The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Only clear solution should be used.
Incompatibilities: The degradation of reconstituted solution is highly pH dependent and the product must therefore only be reconstituted in the specified volume of 0.9% sodium chloride for intravenous use. The reconstituted solution should not be mixed or co-administered in the same infusion set with any other drug.

DR cap: Store at temperatures below 30°C.
Powd for inj: Store at temperature below 30°C, protect from light.
Shelf life after reconstitution: The 5 ml reconstituted solution should be used within 12 hours. The 100 ml reconstituted solution should be used within 8 hours. Store at temperature below 30°C.

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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