ESORAGIM®40

Composition:Each enteric coated tablet contains:
Esomeprazole magnesium trihydrate equivalent to Esomeprazole. . . . . . . . . . . . .40 mg
Presentation:
Alu-Alu blister containing 10 tablets, 3 blisters in a box.
Indications:
Adults: Esoragim 40 is used for the treatment of:
Gastric and duodenal ulcers.
Severe gastroesophageal reflux disease (erosive esophagitis, ulcers or narrowing (stricture) of the esophagus determined by endoscopy).
Prevention of gastric and duodenal ulcers associated with NSAID therapy.
In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori
Pathological hypersecretory conditions including Zollinger-Ellison Syndrome
Children from 12 years of age and over:
This medicine is indicated for the treatment of gastroesophageal reflux disease with esophagitis.

Additional information

Dosage and administration

Dosage:
Adults:
For the treatment of severe gastroesophageal reflux disease with oesophagitis: 1 tablet, once daily for 4 to 8 weeks. If oesophagitis has not healed or symptoms are still persistent, an additional 4-8 weeks treatment is recommended. In severe cases, the dose may be increased to 80 mg per day, in 2 divided doses.
Treatment of gastric and duodenal ulcers caused by Helicobacter pylori (in combination with other reasonable therapies): Esomeprazole is a part of therapy regimens combined with antibiotics, for example, triple therapy (combined with amoxicillin and clarithromycin), the usual dose is 1 tablet once daily for 10 days, (Amoxicillin 1g once, two times daily and clarithromycin 500 mg once, two times daily for 10 days).
Prevention of gastric ulcers in patients with high risk of gastric and duodenal complications, but the treatment with non-steroidal anti-inflammatory drugs is required: 1 tablet, once daily.
Treatment of Zollinger-Ellison syndrome: Dosage will be adjusted individually and depends on the level of gastric acid secretion. The recommended starting dose is 1 tablet, twice daily. Then, adjust the dose as needed. The majority of patients can be controlled on doses between 80 to 160mg esomeprazole daily. With doses above 80mg daily, the dose should be given in 2 divided doses.
Special populations:
Patients with liver impairment: In patients with severe liver impairment, maximum daily dose should not exceed 20mg. Dose adjustment is not required in patients with mild to moderate liver impairment.
Patients with kidney failure and elderly: Dose adjustment is not required.
Children from 12 years of age and over:
Treatment of gastroesophageal reflux disease with oesophagitis: 1 tablet, once daily for 4 weeks. If oesophagitis has not healed or symptoms are still persistent, the same dose of esomeprazole may be given for a further 4 weeks.
Administration:
Esomeprazole is usually taken at least 1 hour before a meal. Swallow Esoragim tablets whole with a glass of water. Do not crush or chew the tablets.

Contraindications

Hypersensitivity to esomeprazole, other proton pump inhibitors or any excipient of this medicine.
Esomeprazole is not combined with nelfinavir and atazanavir.

Warnings and precautions for use

Before starting esomeprazole therapy, the doctor must rule out the possibility of gastric cancer because the medicine can mask the symptoms, and so delay the diagnosis of cancer.
Caution should be exercised when esomeprazole is administered to patients with liver disease, pregnant women or breastfeeding mothers.
Esomeprazole shoul be used with caution in children under 18 years of age because its safety and efficacy have not been established.
Caution should be taken in patients who is treated with esomeprazole for long term (particularly for more than a year) due to the possible occurrence of following risks:
Atrophic gastritis.
Gastrointestinal infections: Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections (such as Salmonella and Campylobacter) and may increase risk of diarrhea.
Risk of fracture: Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of pelvis, wrist and spine fracture due to osteoporosis. The mechanism of this phenomenon has not been explained but may be due to a decrease in insoluble calcium absorption because of increase in gastric pH. It is recommended patients should use the lowest effective dose for the shortest duration possible of PPI therapy appropriate to the condition being treated. Patients at risk of should have an adequate intake of vitamin D and calcium and should be managed according to established treatment guidelines.
Interstitial nephritis has been observed in patients taking PPIs including esomeprazole. Interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue esomeprazole if acute interstitial nephritis develops.
Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like esomeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.
Reduction of vitamin B12 absorption: 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.

Recommendation for pregnancy and breastfeeding

Pregnancy
There are no adequate and well-controlled studies with esomeprazole in pregnant women. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/foetal development. However, esomeprazole should only be used when it it is really necessary during pregnancy.
Breastfeeding
It is not known whether esomeprazole is excreted in human milk. However, the concentration of omeprazole in the human milk after taking 20mg of omeprazole was measured.
Esomeprazole may cause serious undesirable effects in breast-fed infants. A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother and the safety to breast-fed children.

Effects on ability to drive and use machines

There is no evidence to prove esomeprazole has influence on the ability to drive or use machines. However, it should be noted that the medicine can cause headache, dizziness, drowsiness, visual disturbances.

Interactions, incompatibilities of medicine

Effects of esomeprazole on the pharmacokinetics of other medicinal products: Protease inhibitors: 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.
Atazanavir and nelfinavir: Decreased serum levels of these medicines have been reported when given together with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40mg once daily) with atazanavir 300mg/ritonavir 100mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir dose to 400mg did not compensate for the impact of omeprazole on atazanavir exposure.
The co-administration of omeprazole (20mg once daily) with atazanavir 400mg/ritonavir 100mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300mg/ritonavir 100mg qd without omeprazole 20mg once daily. Co-administration of omeprazole (40mg qd) reduced mean nelfinavir AUC, Cmax and Cmin by 36–39% and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75-92%.
Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration of esomeprazole and atazanavir is not recommended and concomitant administration of esomeprazole and nelfinavir is contraindicated.
Tacrolimus: Concomitant administration of esomeprazole and tacrolimus may increase serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.
Methotrexate: When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.
Medicinal products with pH dependent absorption: Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as ketoconazole, itraconazole and erlotinib can decrease and the absorption of digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced.
Medicinal products metabolised by CYP2C19: Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with other medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these active substances 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 30mg esomeprazole resulted in a 45% decrease in clearance of diazepam (a CYP2C19 substrate) Concomitant administration of 40mg esomeprazole 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.
Warfarin: Coadministration of esomeprazole and warfarin results in increase in INR and prothrombin time which may lead to abnormal bleeding and even death. INR and prothrombin times should be frequently monitored while patients are receiving concomitantly esomeprazole and warfarin or other coumarin derivatives.
Clopidogrel: Esomeprazole inhibits CYP2C19, which may reduce the effects of clopidogrel due to its pharmacokinetic interaction with clopidogrel (resulting in reduced plasma concentrations of the active metabolite of clopidogrel) and pharmacodynamic interaction with clopidogrel (reduction in platelet inhibition).
Voriconazole: Concomitant administration of esomeprazole and voriconazole may result in more than doubling of the esomeprazole exposure. In patients with Zollinger-Ellison’s Syndrome, who may require higher doses up to 240mg/day, dose adjustment may be considered.
Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its active metabolite. Therefore, a dose reduction of cilostazol should be considered.
Cisapride: In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t1/2) 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.
Effects of other medicinal products on the pharmacokinetics of esomeprazole Medicinal products which inhibit CYP2C19 and/or CYP3A4: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant 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. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
Medicinal products which induce CYP2C19 and/or CYP3A4: Drugs known to induce CYP2C19 or CYP3A4 or both may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Undesirable effects (ADRs)

In general, esomeprazole is well tolerated when used for both short and long time.
Common, ADR > 1/100 :
– Body as a whole: Headache, dizziness, skin rash.
– Gastrointestinal: Nausea, vomiting, abdominal pain, diarrhea, constipation, flatulence, dry mouth.
Uncommon, 1/1000 < ADR < 1/100:
– Body as a whole: Fatigue, insomnia, drowsiness, rash, pruritus
– Eye disorders
Rare, ADR < 1/1000:
– Body as a whole: Fever, sweating, peripheral edema, sensitivity to light, hypersensitivity reaction (urticaria, angioedema, bronchospasm, anaphylactic shock).
– Central nervous system: Agitation, depression, reversible confusion, hallucinations in severe patients.
– Blood disorders: Agranulocytosis, leucopenia, thrombocytopenia.
– Hepatobiliary: Increased liver enzymes, hepatitis, jaundice, impaired hepatic function.
– Gastrointestinal: Taste disturbance.
– Musculoskeletal: Arthralgia, myalgia.
– Urinary disorders: Interstitial nephritis.
– Skin: Rash maculo-papular, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).
Because of causing the reduction of gastric acidity, the proton pump inhibitors may increase the risk of infections in the gastrointestinal tract.
Guidelines for ADR management: The medicine must be stopped if any of severe undesirable effects occurs.

Overdose and management

– Overdose: There have been no report on the overdose of esomeprazole in human.
– Management: There is no specific antidote for esomeprazole. The treatment should be primarily symptomatic and supportive. Hemodialysis does not increase the elimination of esomeprazole because esomeprazole is highly bound to plasma protein.

Pharmacodynamic properties

Esomeprazole is the S-isomer of omeprazole, and similar to omeprazole it is used in the treatment of gastric and duodenal ulcers, gastroesophageal reflux disease and Zollinger – Ellison syndrome.
Esomeprazole is a proton pump inhibitor that reduces gastric acid secretion by binding to H+/K+ -ATPase (also known as proton pump) in the gastric parietal cell, disabling this enzyme system, prevents the final step of the secretion of hydrochloric acid into the gastric lumen. Thus, esomeprazole has the effect on inhibiting both basal and stimulated acid secretion caused by any agent. The medicine has strong and prolonged effects.
Effects on gastric acid secretion
After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6-7 hours after dosing on day five.
After five days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic gastroesophageal reflux disease patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
When an AUC is used as a parameter for plasma concentrations, it has been shown that there is a relationship between inhibition of acid secretion with concentration and duration of exposure.

Pharmacokinetic properties

After oral administration esomeprazole is rapidly absorbed, with peak plasma levels occurring approximately 1-2 hours after dosing. The bioavailability of esomeprazole increases proportionally when the dose is increased and used repeatedly, 68% with dose of 20mg and 89% with dose of 40mg. Absorption of esomeprazole is decreased and delayed if taken with food. After administration of a single 40mg dose of esomeprazole with meal the AUC is decreased by 33% to 53% compared to fasting conditions. Therefore, esomeprazole should be taken at least one hour before meals. Esomeprazole is bound to plasma proteins by about 97%. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 liters.
Esomeprazole is mainly metabolised in the liver by isoenzyme CYP2C19, belonging to cytochrome P450 enzyme system, to form the inactive hydroxy and desmethyl metabolites. The remaining amount is metabolized via CYP3A4 isoenzyme to form esomeprazole sulfone. When used repeatedly, first-pass hepatic metabolism and clearance of the medicine are decreased, that is possibly because CYP2C19 isoenzyme is inhibited. However, there is no accumulation of esomeprazole during once daily administration.
The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. Almost 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, the remainder is in the faeces. Less than 1% of the parent drug is found in urine.
Special patient populations
CYP2C19 poor metabolisers:
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 40mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%. These findings have no implications for the posology of esomeprazole.
Elderly:
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Hepatic impairment:
The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the area under the plasma concentration-time curve 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.
Renal impairment:
No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Adolescents aged 12-18 years:
Following repeated dose administration of 20mg and 40mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (tmax) in 12 to 18 years old was similar to that in adults for both esomeprazole doses.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 24 months from the manufacture date.
Quality specification: In house specification.