Ezoprole

Esomeprazole magnesium.

Each delayed-release capsule contains: Esomeprazole magnesium 20 mg (equivalent to 21.68 mg Esomeprazole magnesium); Esomeprazole magnesium 40 mg (equivalent to 43.37 mg Esomeprazole magnesium).
20 mg Gastro-resistant Capsule: Slightly pink, size '3' hard gelatin capsule containing white to almost white gastro-resistant pellets.
40 mg Gastro-resistant Capsule: Off-pink, size '1' hard gelatin capsule containing white to almost white gastro-resistant pellets.

Pharmacology: Pharmacodynamics: Esomeprazole is a proton pump inhibitor (PPI) that belongs to the substituted benzimidazole derivative class of antisecretory compounds. Esomeprazole is the S-isomer of omeprazole. It suppresses gastric acid secretion by specific inhibition of the (H⁺, K⁺)-ATPase enzyme system at the secretory surface of the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion.
Pharmacokinetics: Esomeprazole is acid labile and is therefore given as enteric-coated to prevent deterioration in the stomach. Esomeprazole is rapidly absorbed after oral administration and peak plasma concentrations occur within 1 to 2 hours. The bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once daily administration. For the 20 mg, the corresponding values are 50 and 68% respectively. Food delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
The apparent volume of distribution at steady state is approximately 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins.
Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) isoenzyme CYP2C19 to form hydroxy and desmethyl metabolites, which have no effect on gastric acid secretion. The remainder is metabolized by CYP3A4 to form esomeprazole sulfone. There is a decrease in first-pass metabolism and systemic clearance with repeated dosage caused by an inhibition of CYP2C19 isoenzyme. However, there is no accumulation during once daily use.
The total plasma clearance of esomeprazole is approximately 17 L/h after a single dose and 9 L/h after repeated administration. The plasma elimination half-life is approximately 1.3 hours. Almost 80% of an oral dose is excreted as metabolites in the urine, and the remainder is found in the feces.
Special Populations: Poor Metabolizers: Approximately 3% of the Caucasian population and 15% to 20% of Asian population lack a functional CYP2C19 isoenzyme and are called poor metabolizers. In such individuals, the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. At steady state, the ratio of the area under the plasma concentration-time curve (AUC) of esomeprazole in poor metabolizers to the AUC in the rest of the population (extensive metabolizers) is approximately 2:1.
Elderly: The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age). However, increased sensitivity of some older patients cannot be ruled out.
Hepatic Impairment: The metabolism of esomeprazole is decreased in patients with severe hepatic impairment resulting in a 2 to 3 times higher AUC.

Symptomatic treatment of gastroesophageal reflux disease (GERD).
Erosive reflux esophagitis.
Nonsteroidal anti-inflammatory drug (NSAID)-induced gastric and duodenal ulcers and upper gastrointestinal symptoms.
Prevention of gastric and duodenal ulcers associated with low dose aspirin (75-325 mg) therapy.
Helicobacter pylori (H. pylori) associated peptic and duodenal ulcers.
Pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and idiopathic hypersecretion).
Maintenance of hemostasis and prevention of rebleeding of gastric and duodenal ulcers following treatment with esomeprazole intravenous (IV).

General Dosing Recommendations: Esomeprazole should be taken orally, 1 hour before meals. It should not be chewed or crushed. (See table.)

Click on icon to see table/diagram/image

Dosage in Elderly: No dosage adjustment is necessary.
Dosage in Patients with Hepatic Impairment: No dosage adjustment is necessary in patients with mild to moderate liver impairment. However, in patients with severe liver impairment, a maximum daily dose of 20 mg should not be exceeded.
Dosage in Patients with Renal Impairment: No dosage adjustment is necessary.

There is limited information on esomeprazole overdose. A patient who deliberately ingested 280 mg of esomeprazole experienced weakness, loose stools, and nausea. However, single oral doses of 80 mg esomeprazole were uneventful.
Esomeprazole is highly protein bound and is, therefore, not readily dialyzable. If overdose occurs, symptomatic and general supportive treatment should be given.

Hypersensitivity to esomeprazole, other proton pump inhibitors (PPIs), or to any component of the product.
Concomitant use with nelfinavir.

Gastric Malignancy: Symptomatic response to therapy with esomeprazole does not preclude the presence of gastric malignancy, thus the possibility of malignancy should be excluded prior to starting treatment with esomeprazole.
Acute Interstitial Nephritis: Acute interstitial nephritis has been observed in patients taking PPIs including esomeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Esomeprazole should be discontinued if acute interstitial nephritis develops.
Clostridium difficile-Associated Diarrhea: Decreased gastric acidity due to any means, including PPIs, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with PPIs can lead to an increased risk of gastrointestinal infections such as Clostridum difficile, Salmonella, and Campylobacter. PPI therapy, such as esomeprazole, may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD), especially in hospitalized patients, the use of antibiotics, old age, and the presence of co-morbidities. This diagnosis should be considered for diarrhea that does not improve. Patients should use the lowest dose and the shortest duration of PPI therapy appropriate to the condition being treated.
Bone Fracture: PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.
Hypomagnesemia: Symptomatic and asymptomatic hypomagnesemia have been rarely reported in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), physicians may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
Cyanocobalamin (vitamin B₁₂) Deficiency: The prolonged use of PPIs (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B₁₂) caused by hypo- or achlorhydria and may contribute to the development of cyanocobalamin deficiency. Rare reports of cyanocobalamin deficiency occurring with PPI therapy have been reported.
Atrophic Gastritis: Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer.
Helicobacter pylori (H. pylori) Eradication: When prescribing esomeprazole for eradication of H. 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 taking other drugs metabolized via CYP3A4 such as cisapride.
Respiratory Effects: Administration of PPIs has been associated with an increased risk of developing certain infections such as community-acquired pneumonia.
Subacute Cutaneous Lupus Erythematosus (SCLE): PPIs, such as esomeprazole, are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help immediately. Discontinuation of esomeprazole treatment should be considered.
Effects on Ability to Drive and Use Machines: Esomeprazole may cause somnolence, dizziness, vertigo, and visual disturbances. Patients should exercise caution when driving vehicles or operating machinery.
Use in Children: The safety and efficacy of esomeprazole in pediatric patients 1 to 17 years of age and 1 month to less than 1 year of age have been established for short-term treatment of GERD and erosive esophagitis, respectively. However, the safety and efficacy of esomeprazole in pediatric patients less than 1 month have not been established.
Use in the Elderly: No significant differences in safety and efficacy were observed between the elderly and younger individuals. However, increased sensitivity of some older individuals cannot be ruled out.
Benefits of esomeprazole treatment should be weighed against the increased risk of fractures as patients in this group may already be at high risk for osteoporosis-related fractures. Patients should be carefully monitored if esomeprazole treatment is required.

Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Esomeprazole should only be used in pregnant women or women suspected of being pregnant if the potential benefits outweigh the potential risks of treatment.
Lactation: Esomeprazole is likely present in human milk. Esomeprazole is the S-isomer of omeprazole and limited data indicate that maternal doses of omeprazole 20 mg daily produce low levels in human milk. Caution should be exercised when esomeprazole is administered to a breastfeeding woman.

The most frequently reported adverse effects with esomeprazole include headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth.
Infections and Infestations: Fungal infection, herpes simplex, moniliasis, viral infection.
Neoplasms benign, malignant, and unspecified (including cysts and polyps): Benign gastrointestinal neoplasm, carcinoid tumor of the stomach, fundic gland polyps (benign), neoplasm progression.
Blood and lymphatic system disorders: Agranulocytosis, anemia, bilirubinemia, cervical lymphadenopathy, hypochromic anemia, leukocytosis, leukopenia, pancytopenia, thrombocytopenia.
Immune system disorders: Anaphylactic reaction/shock, angioedema, systemic lupus erythematosus.
Endocrine disorders: Goiter, hyperparathyroidism, hypothyroidism.
Metabolism and nutrition disorders: Anorexia, dehydration, facial edema, generalized edema, hypercholesterolemia, hyperuricemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, increased appetite, leg edema, peripheral edema, thirst, vitamin B₁₂ deficiency.
Psychiatric disorders: Aggression, agitation, anxiety, apathy, confusion, depression, hallucinations, insomnia, nervousness, sleep disorder, somnolence.
Nervous system disorders: Carpal tunnel syndrome, dizziness, hyperesthesia, hypoesthesia, migraine, paresthesia, tremor.
Eye disorders: Blurred vision, conjunctivitis, visual field defect.
Ear and labyrinth disorders: Earache, ear infection, otitis media, tinnitus, vertigo.
Cardiac disorders: Chest pain, substernal chest pain, tachycardia.
Vascular disorders: Epistaxis, hot flushes, hypertension.
Respiratory, thoracic, and mediastinal disorders: Asthma, bronchitis, bronchospasm, cough, dyspnea, parosmia, pharyngitis, pharyngolaryngeal pain, respiratory tract infection, rhinitis, rhinorrhea, sinusitis, tachypnea.
Gastrointestinal disorders: Abdominal rigidity, Barrett's esophagus, Clostridium difficile-associated diarrhea, defecation urge, duodenitis, dyspepsia, dysphagia, enlarged abdomen, epigastric pain, erosive gastritis, eructation, esophageal disorder, gastric retention, gastric ulcer, gastritis, gastroenteritis, gastrointestinal candidiasis, gastrointestinal dysplasia, gastrointestinal hemorrhage, gastrointestinal tract mucosal discoloration, gingival abscess, hiccup, melena, microscopic colitis, pancreatitis, regurgitation, stomatitis, taste disturbance, taste loss, tooth disorder, ulcerative stomatitis, vomiting.
Hepatobiliary disorders: Hepatic encephalopathy, hepatic failure, hepatitis with or without jaundice, increased liver enzymes.
Skin and subcutaneous tissue disorders: Acne, alopecia, dermatitis, erythema multiforme, erythematous rash, maculopapular rash, photosensitivity, pruritus, rash, skin inflammation, Stevens-Johnson syndrome (SJS), subacute cutaneous lupus erythematosus (SCLE), tongue edema, toxic epidermal necrolysis (TEN), urticaria.
Musculoskeletal and connective tissue disorders: Arthralgia, arthritis, arthropathy, back pain, bone fracture, cramps, fibromyalgia syndrome, fracture of the hip, wrist, or spine, hypertonia, muscle spasms, myalgia, muscular weakness, osteoporosis, polymyalgia rheumatica, rigors.
Renal and urinary disorders: Albuminuria, cystitis, dysuria, glycosuria, hematuria, interstitial nephritis, polyuria, proteinuria, renal failure, urinary frequency, urinary tract infection.
Reproductive system and breast disorders: Dysmenorrhea, genital moniliasis, gynecomastia, impotence, menstrual disorder, vaginitis.
General disorders and administration site conditions: Asthenia, fatigue, fever, flu-like disorder, hernia, increased sweating, malaise, pain.
Investigations: Increased alkaline phosphatase, increased serum gastrin, increased serum glutamic oxaloacetic transaminase, increased serum glutamic pyruvic transaminase, weight gain/loss.
Injury, poisoning and procedural complications: Postoperative pain.

Antiretroviral Drugs: Concomitant use of atazanavir, nelfinavir, rilpivirine, saquinavir or raltegravir with PPIs is not recommended. Esomeprazole is expected to substantially decrease atazanavir, nelfinavir, and rilpivirine plasma concentrations, which may result in loss of therapeutic effect and development of drug resistance. In contrast, coadministration of saquinavir or raltegravir with PPIs is expected to increase saquinavir or raltegravir concentrations, which may increase toxicity and require dose reduction.
pH-dependent Drugs: Esomeprazole may reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. As with other drugs that decrease intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, nelfinavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) may also decrease, while the absorption of drugs such as digoxin may increase during treatment with esomeprazole.
Digoxin: Coadministration of digoxin with esomeprazole may increase the systemic exposure of digoxin. Therefore, patients should be carefully monitored when digoxin is taken concomitantly with esomeprazole.
Mycophenolate mofetil (MMF): Coadministration of esomeprazole in healthy patients and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure in organ rejection has not been established in transplant patients receiving esomeprazole and MMF.
Drugs Affecting/Metabolized by Hepatic Microsomal Enzymes: Esomeprazole is metabolized in the liver through CYP2C19 and CYP3A4. Drugs known to inhibit CYP2C19 or CYP3A4 or both (e.g., clarithromycin and voriconazole) may increase the plasma concentrations of esomeprazole by decreasing the rate of its metabolism.
In contrast, drugs known to induce CYP2C19 or CYP3A4 or both (e.g., rifampicin and St. John's Wort) may decrease the plasma concentrations of esomeprazole by increasing the rate of its metabolism.
Diazepam: Concomitant administration of esomeprazole and diazepam may decrease diazepam clearance by 45%.
Warfarin: Increased international normalized ratio (INR) and prothrombin time have been reported in patients receiving PPIs and warfarin concomitantly. Since such increases may lead to abnormal bleeding and even death, patients being treated with PPIs and warfarin should be monitored for increases in INR and prothrombin time.
Tacrolimus: Concomitant administration of esomeprazole and tacrolimus may increase the plasma concentrations of tacrolimus. The plasma concentrations and creatinine clearance of tacrolimus should be monitored. The dosage of tacrolimus may be adjusted if necessary.
Citalopram, Imipramine, Clomipramine, Cilostazol and Phenytoin: Concomitant administration of esomeprazole (a CYP2C19 inhibitor) with drugs that are metabolized by CYP2C19 (e.g., citalopram, imipramine, clomipramine, cilostazol, and phenytoin) may increase the plasma concentrations of these drugs. Dosage adjustment is recommended.
Clopidogrel: Concomitant use of esomeprazole with clopidogrel reduces exposure to the active metabolite of clopidogrel and decreases platelet inhibitory effects.
Citalopram/Escitalopram: Coadministration of esomeprazole with citalopram doubles the AUC of the S-isomer of citalopram (escitalopram) but did not affect its R-isomer. Dosage adjustment of citalopram/escitalopram may be necessary.
Drugs that Cause Hypomagnesemia: Possible increased risk of hypomagnesemia; Monitoring of magnesium levels prior to and during PPI treatment should be considered in patients expected to be on prolonged PPI treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., loop or thiazide diuretics).
Methotrexate: Concomitant administration of PPIs and methotrexate, primarily at high doses, may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicity. Temporary PPI withdrawal may be considered in patients receiving high-doses of methotrexate.
Sucralfate: Concomitant administration of esomeprazole with sucralfate resulted in delayed absorption and decreased bioavailability of esomeprazole. PPIs should be administered at least 30 minutes before sucralfate.
Cisapride: Concomitant administration of esomeprazole with cisapride increased the AUC of cisapride by 32% and prolonged the elimination half-life by 31% but no significant increase in peak plasma concentrations of cisapride.
Laboratory Interactions: During treatment with antisecretory drugs, chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumors. Esomeprazole treatment should be stopped 14 days before CgA measurement to avoid this interference.

Store in the original packaging at temperatures not exceeding 30°C.
Protect from moisture.

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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