Esomeprazole
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Esomeprazole - Pubdrug Esomeprazole From Pubdrug Jump to: , Certified You are reading a certified PubDrug document. This document is complete and accurate to the best of the knowledge of the author and reviewer. This document cannot be edited without being unlocked by the PubDrug admin. Edits or updates may be recommended under the Discussion tab for this document. Authored by: Certified by: 14:58, 24 April 2007 (PDT) Esomeprazole Quick Reference IUPAC Name (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl]-3H-benzoimidazole Chemical Information Empirical Formula C 17 H 19 N 3 O 3 S Molecular Weight 345.417 General Drug Information Classification Proton Pump Inhibitor (PPI) Schedule How Supplied Oral Capsules: Delayed-Release 20mg, Delayed-Release 40mg; Unit dose packages of 20 and 40mg for oral suspension; 20 and 40mg powder for intravenous injection Trade Names Nexium B Breast Feeding Concentrations of esomeprazole have been found in breast milk. Caution should be used. Generic Availability Generic not available Patent Expiration Date Administration Information Routes Oral, Nasogastric/Gastric Tube, Intravenous Method Oral: taken once daily one hour before meals Nasogastric/ Gastric tube: given once daily Intravenous injection: infused once daily for 3-30 minutes with or without food for 5 days Information F = 64% (single dosing) F = 90% (multiple dosing) F = 100% (Intravenous dosing) C max = 4.7-2.1 hours (Oral dosing) C max = 3.9-7.5 hours (Intravenous dosing) t max = 1.5 hours (Oral dosing) Vd = 16 L (Oral and Intravenous dosing) Protein binding ~ 98% Hepatic via CYP2C19 and 3A4 enzymes to hydroxy, desmethyl, and sulfone metabolites (all inactive) T 1/2 = 1_1.5 hours (Oral and Intravenous dosing) 80% Urine 20% Feces Contents Brand/Trade Names of Drug Nexium Generic Name of Drug Esomeprazole magnesium (es oh ME pray zol) Description Esomeprazole belongs to a class of medications know as (PPI's). PPI's, via the inhibition of H+/K+ ATPase enzyme pumps located in the gastric lumen, decrease the amount of gastric acid produced. Esomeprazole consists only of the active isomer (S-isomer), whereas its counterpart, contains the active and in-active isomers (R and S-isomers). Studies have shown that a decrease in the amount of gastric acid produced was beneficial for patients with Erosive Esophagitis, Symptomatic Gastroesophageal Reflux Disease (GERD), NSAID-Associated Gastric Ulcers, Heliocobacter pylori (H. pylori) infections, and Zollinger-Ellison Syndrome. In patients with gastro-esophageal reflux disease (GERD), PPI_s have been shown to relieve patients of GERD symptoms. In other cases, such as patients with h. pylori infections or the development of ulcers with the use of NSAID_s, PPI_s have again proven to be efficacious in symptomatic and gastric damage relief. Mechanism of action Esomeprazole, like other PPI's, is a prodrug that is activated in an acidic environment to it's active form (sulfenamide). The active form of the prodrug creates a covalent bond to H+/K+ ATPase pumps located on parietal cells in the gastric lumen. H+/K+ ATPase pumps are involved in the final step of the acid secretion pathway. This bond irreversibly inhibits the subsequent release of hydrogen ions. Inhibition of acid production is maintained until new H+/K+ ATPase pumps are regenerated (~18 hours). Time Required for Therapeutic Response Initial: ~1 day Maximum: ~7 days Pharmacokinetics Absorption Esomeprazole, intended for the oral route of administration, is formulated with an enteric coating to prevent rapid dissolution in the acidic environment of the gastric cavity. The different strengths of oral esomeprazole (20mg and 40mg) create the ranges seen in Cmax, Tmax and AUC. A single 40mg oral dose, taken without food, reaches its peak of 4.7 _mol/L (Cmax) within 1.5 hours (Tmax) with a bioavailability of 64%. The plasma concentration-time curve (AUC) for this single dose is 4.32 _mol*h/L. After multiple doses in fasting conditions, bioavailability increases to ~90% and the AUC increases to 11.2 _mol*h/L. The AUC decreases by 43-53% when a single dose is taken with food. Due to the differences in isomeric composition, the AUC of Esomeprazole is 80% higher that that of . This is due to a decrease in the clearance and first-pass metabolism of the S-isomer. Intravenous forms of esomeprazole have a slightly different pharmacokinetic profile than the oral forms. The different strengths of IV esomeprazole (20mg and 40mg) create the ranges seen in Cmax and AUC. After the IV administration of a 40mg dose, given once daily for a total of 5 days, the AUC is 16.2 _mol*h/L with a peak concentration (Cmax) of 7.51 _mol/L. Distribution Esomeprazole as an apparent volume of distribution of 16 L. Additionally, esomeprazole is approximately 97% protein bound. This applies to both the oral and intravenous forms. Metabolism Esomeprazole metabolism is mediated via the cytochrome P450 enzyme system (CYP450). The hydroxyl and desmethyl metabolites are formed by the CYP219 isoenzyme, while the sulphone metabolite is formed via the CYP3A4 enzyme. All metabolites formed are inactive. Excretion The inactive metabolites of esomeprazole are mainly renally excreted (80%) with some fecal elimination (20%). A minimal amount of the active parent drug is excreted in the urine (1%). The elimination half life for both the oral and intravenous forms ranges from 1-1.5 hours, with a slightly longer half life with the oral forms of esomeprazole. Elimination is complete with no accumulation of drug. Special Population Pharmacokinetics Renal Insufficiency Due to the insignificant amount of renal elimination of active esomeprazole, there are expected to be no differences between healthy and renally impaired patients. No dosage adjustments are necessary. Hepatic Insufficiency Patients with sever hepatic insufficiency (Child Pugh Class C) have been shown to have a 2-3 times higher AUC of esomeprazole than those with normal hepatic function. Those with mild-moderate hepatic insufficiency (Child Pugh Class A and B) reported no change in AUC. Hemodialysis Unavailable Geriatric Both AUC and C max were higher in elderly patients, but this was without any significance. No dosage adjustments necessary. Pediatric Any changes in patients ages 12-17 years old were similar to the changes seen in adult patients. No dosage changes are necessary. Gender In female patients, AUC and C max were slightly higher than males, but without any significance. No dosage changes are necessary. Indications/Dosage FDA Approved Indications (Oral) (GERD) with or without Erosive NSAID-associated Gastric Ulcer Prophylaxis Eradication for Ulcer Prophylaxis Duodenal Ulcer FDA Approved Indications (Intravenous) (GERD) with a history of Erosive Dosage Note: The use of 40mg over 20mg has no proven benefit. Oral Gastro-esophageal Reflux Disease (GERD) with or without Erosive Esophagitis Healing/Symtomatic Relief 20-40mg once daily for 4-8 weeks. An additional 4-8 weeks of therapy if initial 4-8 weeks was ineffective. Maintenance 20-40mg once daily for up to 6 months. Studies have not been carried out past 6 months. NSAID-associated Gastric Ulcer Prophylaxis 20-40mg once a day. Studies have been done for up to 26 weeks of use. Heliocobacter pylori (H.pylori) Eradication for Ulcer Prophylaxis 40mg once a day for ~4weeks. Eradication of H.pylori is seen when esomeprazole is used in combination with and . Zollinger-Ellison Syndrome Typical dose is 40mg twice daily. Patients have been show to see therapeutic results with daily dosages ranging from 80-240mg. Duodenal Ulcer 40mg once a day for ~4weeks. Eradication of H.pylori is seen when esomeprazole is used in combination with and . Intravenous Gastroesophegeal Reflux Disease (GERD) with a history of Erosive Esophagitis 20-40mg once daily infusions given over 3-30 minutes for up to 10 days. Change to oral form if possible after 10 days. Maxium Dosage Limits Adults (PO/IV) 40mg/day Adults (Zollinger-Ellison Syndrome) 240mg/day Elderly (PO/IV) 40mg/day Elderly (Zollinger-Ellison Syndrome) 240mg/day Adolescents > 17 years (PO) 40mg/day Children and Adolescents 12-17 years (PO) 40mg/day Children <12 years Safe and effective use have not been established Administration Capsule Route: Oral Method: Swallow capsule whole with a full glass of water or capsule can be opened and sprinkled/mixed with applesauce. Capsule should be taken once daily and is best if daily dose is taken one hour prior to a meal. Special considerations: Applesauce must be at room temperature and should be administered right after mixing. Route: Nasogastric Tube Method: Open capsule and place granules into a catheter tipped syringe. Add 50ml of water to syringe, replace the plunger and shake contents of syringe for ~15 seconds. Attach syringe to nasogastric tube and inject syringe contents. Flush nasogastric tube with additional water. This should be done once daily. Special considerations: Do not administer contents of syringe if granules are dissolved or disintergrated. Powder for oral solution Route: Oral Method: Mix contents of one packet with 15ml of water, stir and let sit for a couple of minutes to thicken. Drink suspension within 30 minutes of making. If any residual suspension remains, add more water and drink immediately. Route: Nasogastric Tube Method: In a catheter tipped syringe, add the contents of one packet to 15ml of water, shake and let sit for a couple of minutes to thicken. Shake the syringe and inject into nasogastric tube. Refill the syringe with 15ml of water and flush the NG- tube. Suspension must be administered within 30 minutes of making. Powder for Intravenous Injection Route: Intravenous Method: Reconstitute the powder with 5ml of 0.9% Sodium Chloride Injection, USP. Withdraw 5ml of solution and inject intravenously over no less then 3 minutes. This should be stored at room temperature and should be administered within 12 hours of making. Powder for Intravenous Infusion Route: Intravenous Method: Reconstitute the powder with 5ml of 0.9% Sodium Chloride Injection, USP, Lactated Ringer_s Injection, USP or 5% Dextrose Injection, USP. The final admixture should then be diluted to a final volume of 50ml and can then be infused intravenously over 10-30 minutes. This should be stored at room temperature. If using 0.9% Sodium Chloride Injection or Lactated Ringer_s Injection for dilution, the admixture should be administered within 12 hours of making. If using 5% Dextrose Injection for dilution, the admixture should be administered within 6 hours. Monitoring Parameters Liver Function Tests (LFT's) Esomeprazole is hepatically metabolized. The occurrence of changes in liver function tests was seen to be <1%. Monitoring of LFT_s may be reserved for those with suspected hepatic dysfunction. Contraindications/Precautions Contraindications Benzimidazole hypersensitivity Precautions Gastric Malignancy Pregnancy: Although studies have been done in rats without any teratogenic outcomes, no studies have been performed in pregnant females. Caution is advised with the use of esomeprazole during pregnancy. Breast Feeding: Concentrations of esomeprazole have been found in breast milk. Caution should be used. Pregnancy indications Pregnancy Category: B To date, there have been teratology studies done in rats without any shown harm to the fetus. This study, however, has not been performed in pregnant females but there have been sporadic reports of congenital abnormalities in infants born to mothers receiving esomeprazole therapy. Breast-feeding indications Secretion into breast milk: There are no studies of the secretion of esomeprazole into breast milk, although, concentrations of the drug have been found in breast milk. Because there have been no studies done in nursing females, caution is advised when using esomeprazole in nursing mothers. Discontinuation of the medication should be attempted if the nursing mother has indication to do so. Drug-Drug Interactions Esomeprazole Drug/Drug Interaction Chart Severity Level Increased Effect/Toxicity Decreased Effect 4 None Known 3 , , , , , H2 Blockers 2 , , , , antimuscarinics , , , , 1 , , , , , , (fosphenytoin) , , , , , , Combination therapy with and , , , , , , , , , , (vitamin B12) , , , Drug-Food-Herb Interactions Esomeprazole Drug/Food/Herb Interaction Chart Severity Level Increased Effect/Toxicity Decreased Effect 4 None Known None Known 3 None Known None Known 2 None Known None Known 1 None Known None Known Adverse Reactions/Side Effects Esomeprazole is generally well tolerated. Most adverse events have <1% occurance. It appears that CNS affects (headaches) are more common with IV dosage forms. The most common adverse event for all dosage forms was diarrhea (1-2.5%) and nausea (0-7%). Esomeprazole Adverse Reactions Chart Incidence Body System Adverse Reactions > 10 % CNS Headache (IV 11%/oral 3-6%) 2-10% CNS Dizziness (3%) CV None listed Dermatologic Injection site reaction (IV 2%) GI Flatulence (10%), nausea (I.V. 6%/oral 2%), abdominal pain (IV 6%/oral 3-4%), diarrhea (4%), xerostomia (I.V. 4%/oral _1%), dyspepsia (0-6%), constipation (3%) GU None listed Neuromuscular & skeletal None listed Respiratory Sinusitis (I.V. 2%), respiratory infection (IV 1%) Misc None listed < 2% All abdominal pain, general/peripheral/facial edema, allergic reaction, back pain, chest pain, asthenia, hot flushes, fatigue, fever, flu-like disorder, malaise, rigors, pain, hypertension, tachycardia, goiter, bowel irregularity, consstipation aggravated, dyspepsia, dysphagia, epigastric pain, erucatation, esophageal disorder, frequent stools, GI hemorrhage, diccup, mouth/rectal/pharynx/tongue disorder, serum gastrin increased, ulcerative stomatitis, vomiting, earache, tinnitus, anemia, cervical lymphoadenopathy, epistaxis, leukocytosis, leudopenia, thrombocytopenia, bilirubinemia, hepatic function abnormal, SGOT/SGPT increased, glycosuria, hyperuricemia, hyponatermia, increase alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase/decrease, arthralgia, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica, anorexia, apathy, appetite increased, confusion, depression aggravated, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, paresthesia, somnolence, vertigo, visual field defect, dysmenorrhea, vafinitis, coughing, acne, dermatitis, pruritis, rash, skin inflammation, increased sweating, urticaria, otitis media, taste loss, abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, polyuria, conjuctivitis Overdosage Measures Dosages of around 510 mg/kg were observed to be toxic in rats. Signs of toxicity seen in rats included changes in respiratory frequency, tremor, reduced motor activity, ataxia, and intermittent clonic convulsions. In humans, doses greated than 120 times greater than the recommended dosages created toxicity such as confusion, drowsiness, blurred vision, tachcardia, nausea, flushing, headache and dry mouth. Toxicity was rarely seen when doses were kept within recommended therapeutic ranges. Overall, esomeprazole is well tolerated. Product Information and Distribution Esomeprazole Product Availability Information Name Manufacturer Dosage Form Strength Quantity NDC Storage Nexium AstraZeneca Oral Delayed Release Capsules 30 00186-5020-31 25_C (77_F) 100 00186-5022-28 90 00186-0520-54 1000 00186-5020-82 30 00186-5040-31 100 00186-5042-28 90 00186-5040-54 1000 00186-5040-82 Delayed-Release Powder for Suspension 20 mg unit dose packages of 30 00186-4020-01 40 mg unit dose packages of 30 00186-4040-01 IV Powder for Injection 20 mg 1 carton of 10 vials (each vial=20mg of esomeprazole) 00186-6020-01 40 mg 1 carton of 10 vials (each vial=40mg of esomeprazole) 00186-6040-01 Manufacturers/Distributors AstraZeneca LP, Wilmington, DE Inactive ingredients glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl cirtate Pharmacogenomic Information References _ _ _ _ _ _ _ _ _ Clinical Pharmacology: Nexium Monograph. 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Wilmington DE: AstraZeneca Pharmaceuticals LP; 2002 Oct Cedax_(ceftibuten) package insert. Morrisville, NC: Biovail Pharmaceuticals, Inc.; 2002 Mar. _ _ Focalin_ XR(dexmethylphenidate extended-release) package insert. East Hanover, NJ: Novartis Pharmaceutical Corp.; 2006 August. Oosterhuis B, Jonkman JH, Andersson T, et al. Minor effect of multiple dose omeprazole on the pharmacokinetics of digoxin after a single oral dose. Br J Clin Pharm 1991;32:569_72. Sustiva_ (efavirenz) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2007 Jan. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994;120:211_5. Prevacid_ (lansoprazole) package insert. Lake Forest, IL:TAP Pharmaceuticals Inc.; 2004 Jun. 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