Esomeprazole

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Esomeprazole quick reference

Esomeprazole
Esomeprazole general drug information
 Pronunciation ess oh MEH pray zol (.wav file)
 Trade Name(s) Nexium
 How Supplied Capsules: 20 mg, 40 mg
Powder for oral suspension: 20 mg, 40 mg
Powder for IV injection: 20 mg, 40 mg
 Generic Availability No generics available
 Patent Expiry Date April 19, 2007
 Classification Proton pump inhibitor
 Schedule Rx
 Pregnancy Category B
 Breast-feeding Concentrations of esomeprazole have been found in breast milk. Caution should be used.
Esomeprazole chemical information
 IUPAC Name (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)

methylsulfinyl]-3H-benzoimidazole

 Empirical Formula C17H19N3O3S
 Molecular Weight 345.417 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Esomeprazole belongs to a class of medications known as proton pump inhibitors (PPIs). PPIs, 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, omeprazole, contains both active and inactive isomers (R- and S-isomers).[1]

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, Helicobacter pylori (H. pylori) infections, and Zollinger-Ellison Syndrome.[2] In patients with GERD, PPIs 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 NSAIDs, PPIs have again proven to be efficacious in symptomatic and gastric damage relief.[3][4]

Mechanism of Action

Esomeprazole, like other PPIs, is a prodrug that is activated in an acidic environment to its 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).[1][3]

Time Required for Therapeutic Response

  • Initial: ~1 day[5]
  • Maximum: ~7 days[5]

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 (20 mg and 40 mg) create the ranges seen in Cmax, Tmax and AUC. A single 40 mg oral dose, taken without food, reaches its peak of 4.7 µmol/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 µmol*h/L. After multiple doses in fasting conditions, bioavailability increases to ~90% and the AUC increases to 11.2 µmol*h/L. The AUC decreases by 43-53% when a single dose is taken with food.[1][2] Due to the differences in isomeric composition, the AUC of esomeprazole is 80% higher that that of omeprazole. This is due to a decrease in the clearance and first-pass metabolism of the S-isomer.[1]

Intravenous forms of esomeprazole have a slightly different pharmacokinetic profile than the oral forms. The different strengths of IV esomeprazole (20 mg and 40 mg) create the ranges seen in Cmax and AUC. After the IV administration of a 40 mg dose, given once daily for a total of 5 days, the AUC is 16.2 µmol*h/L with a peak concentration (Cmax) of 7.51 µmol/L.[6][7]

Distribution
Esomeprazole has 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 CYP2C19 isoenzyme, while the sulphone metabolite is formed via the CYP3A4 enzyme. All metabolites formed are inactive.[1][2]

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.[2][8]



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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.[2]
  • Hepatic insufficiency: Patients with severe 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 Classes A and B) reported no change in AUC.[2][9]
  • Hemodialysis: Unavailable.
  • Geriatric: Both AUC and Cmax were higher in elderly patients, but this was without any significance. No dosage adjustments necessary.[2]
  • Pediatric: Any changes in patients ages 12-17 years old were similar to the changes seen in adult patients. No dosage changes are necessary.[2]
  • Gender: In female patients, AUC and Cmax were slightly higher than males, but without any significance. No dosage changes are necessary.[2]

Indications and Dosages

FDA Approved Indications

Gastroesophegeal reflux disease (GERD) with or without erosive esophagitis (oral, IV)[1][2][6]

  • Healing/symptomatic relief:
    • 20-40 mg QD for 4 to 8 weeks
    • Additional 4 to 8 weeks of therapy is indicated if initial therapy is ineffective.
  • Maintenance dose:
    • 20-40 mg QD for up to 6 months.
    • Studies have not been carried out past 6 months.
  • Intravenous dose:
    • 20-40 mg QD infusions given over 3-30 minutes for up to 10 days.
    • Convert patient to oral dosage form if possible after 10 days.

NSAID-associated gastric ulcer prophylaxis (oral)[2]

  • Maintenance dose:
    • 20-40 mg QD.
    • Studies have been done for up to 26 weeks of use.

Helicobacter pylori (H. pylori)-associated duodenal ulcer (oral)

  • Maintenance dose:
    • 40 mg QD for ~4 weeks.
    • Eradication of H.pylori is seen when esomeprazole is used in combination with amoxicillin and clarithromycin.

Zollinger-Ellison Syndrome (oral)[2]

  • Maintenance dose:
    • Typical dose is 40 mg BID.
    • Patients have been shown to see therapeutic results with daily dosages ranging from 80-240 mg.

Non-FDA Approved Indications

  • H. pylori-associated gastric ulcer
  • nephropathic cystinosis
  • pyrosis (heartburn)

Dosage Adjustment

Hepatic insufficiency: Do not exceed 20 mg/day in patients with severe hepatic insufficiency (Child Pugh Class C).

Dosage Limits

Note: The use of 40 mg esomeprazole over 20 mg has no proven benefit.[2]

  • Adults (18 years and up): 40 mg/day (for Zollinger-Ellison Syndrome, 240 mg/day)[1]
  • Elderly: 40 mg/day (for Zollinger-Ellison Syndrome, 240 mg/day)[1]
  • Adolescents and children ages 12-17 years: 40 mg/day PO[1]
  • Children ages <12 years: Safe and effective use has not been established.


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Administration

  • Route: Oral (capsule)[2]
  • Method:
    • Swallow capsule whole with a full glass of water or capsule can be opened and sprinkled/mixed with room temperature applesauce.
    • Capsule should be taken once daily and is best if daily dose is taken one hour prior to a meal.
  • Route: Oral (powder for oral suspension)[2]
  • Method:
    • Mix contents of one packet with 15 ml (one tablespoonful) 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 (capsule)[2]
  • Method:
    • Open capsule and place granules into a catheter-tipped syringe. Add 50 ml of water to syringe, replace the plunger and shake contents of syringe for about 15 seconds.
    • Attach syringe to NG tube and inject syringe contents. Flush NG tube with additional water.
    • Do not administer contents of syringe if granules are dissolved or disintergrated.
  • Route: Nasogastric tube (powder for oral suspension)[2]
  • Method:
    • In a catheter-tipped syringe, add the contents of one packet to 15 ml of water, shake, and let sit for a couple of minutes to thicken.
    • Shake the syringe and inject into NG tube. Refill the syringe with 15ml of water and flush the NG tube.
    • Suspension must be administered within 30 minutes of making.
  • Route: Intravenous (IV powder)[6]
  • Method:
    • Reconstitute the powder with 5 ml of 0.9% Sodium Chloride Injection, USP, Lactated Ringers Injection, USP, or 5% Dextrose Injection, USP.
    • The final admixture should then be diluted to a final volume of 50 ml and can be infused intravenously over 10-30 minutes.
    • If using 0.9% Sodium Chloride Injection or Lactated Ringers 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.
    • Mixture should be stored at room temperature.

Monitoring Parameters

  • Liver function tests (LFTs)
    • Esomeprazole is hepatically metabolized. The occurrence of changes in liver function tests was seen to be <1%. Monitoring of LFTs may be reserved for those with suspected hepatic dysfunction.[2]

Contraindications/Precautions

Contraindications

  • Benzimidazole hypersensitivity[2]

Precautions

  • Gastric malignancy[1]
  • 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.[2]
  • Breastfeeding: Concentrations of esomeprazole have been found in breast milk. Caution should be used.[2]

Pregnancy indications

Category B

To date, there have been teratology studies done in rats without any harm to the fetus. Studies have not been performed in pregnant females but there have been sporadic reports of congenital abnormalities in infants born to mothers receiving esomeprazole.[2]

Breast-feeding indications

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.[2]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Esomeprazole is generally well-tolerated. Most adverse events have <1% occurence. 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%).[2][8]

Esomeprazole Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Headache (IV 11%/oral 3-6%)
1-10% CNS Dizziness (3%)
Dermatologic Injection site reaction (IV 2%)
GI Flatulence (10%), nausea (IV 6%/oral 2%), abdominal pain (IV 6%/oral 3-4%), diarrhea (4%), xerostomia (IV 4%/oral ≥1%), dyspepsia (0-6%), constipation (3%)
Respiratory Sinusitis (IV 2%), respiratory infection (IV 1%)
<1% 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, constipation aggravated, dysphagia, epigastric pain, eructation, esophageal disorder, frequent stools, GI hemorrhage, hiccup, mouth/rectal/pharynx/tongue disorder, serum gastrin increased, ulcerative stomatitis, vomiting, earache, tinnitus, anemia, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia, bilirubinemia, hepatic function abnormal, SGOT/SGPT increased, glycosuria, hyperuricemia, hyponatremia, increased 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, vaginitis, coughing, acne, dermatitis, pruritis, rash, skin inflammation, increased sweating, urticaria, otitis media, taste loss, abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturation 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.[2]
Treatment:

  • n/a
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
20 mg capsule purple/2 yellow bands capsule NEXIUM 20 mg
40 mg capsule purple/3 yellow bands capsule NEXIUM 40 mg
20 mg powder for oral suspension yellow powder n/a
40 mg powder for oral suspension yellow powder n/a
20 mg IV powder for injection white powder n/a
40 mg IV powder for injection white powder n/a
  • Inactive ingredients for capsules: D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, gelatin, glyceryl monostearate, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, magnesium stearate, methacrylic acid copolymer, n-butyl alcohol, polyvinyl pyrrolidone, propylene glycol, shellac, sodium hydroxide, sugar spheres, talc, titanium dioxide, triethyl citrate
  • Inactive ingredients for oral powder for suspension: citric acid, crospovidone, dextrose, hydroxypropyl cellulose, iron oxide, xanthan gum
  • Inactive ingredients for IV powder for injection: disodium edetate, sodium hydroxide

Patient Information

  • See administration section for administration information.
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References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Clinical Pharmacology: Nexium Monograph. Available at: www.clinicalpharmacology.com
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 Nexium (esomeprazole magnesium) package insert for PO use Wilmington, DE; AstraZeneca; 2006 October.
  3. ↑ 3.0 3.1 Integrative Inflammation Pharmacology: Peptic Ulcer Disease. Eds: Golan DE., et al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. pgs: 389-69. Baltimore, Lippincott Williams & Wilkins.
  4. ↑ Yeomans, Neville D.; Tulassay, Zsolt; Juhasz, Laszlo; Racz, Istvan; Howard, John M.; van Rensburg, Christoffel J.; Swannell, Anthony J.; Hawkey, Christopher J. A Comparison of Omeprazole with Ranitidine for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs.N Engl J Med 1998;338:719-726.
  5. ↑ 5.0 5.1 Simon,B; Müller, P; Pascu, O. Intra-oesophageal pH profiles and pharmacokinetics of pantoprazole and esomeprazole: a crossover study in patients with gastro-oesophageal reflux disease. European Journal of Gastroenterology & Hepatology. Volume 15(7), July 2003, pp 791-799.
  6. ↑ 6.0 6.1 6.2 Nexium (esomeprazole magnesium) package insert for IV use. Wilmington, DE; AstraZeneca; 2006 October.
  7. ↑ Wilder-Smith,C; Bondarov,P; Lundgren,M. Intravenous esomeprazole (40 mg and 20 mg) inhibits gastric acid secretion as effectively as oral esomeprazole: results of two randomized clinical studies.European Journal of Gastroenterology & Hepatology. Volume 17(2), February 2005, pp 191-197.
  8. ↑ 8.0 8.1 Lexi-Comp (2003). Drug Information Handbook. 11th Edition., APhA
  9. ↑ Sjövall,H; Björnsson,E; Holmberg,J; Hasselgren,G; Pharmacokinetic study of esomeprazole in patients with hepatic impairment. European Journal of Gastroenterology & Hepatology. Volume 14(5), May 2002, pp 491-496

PUBMED References

Efficacy Trial Articles

  1. Yeomans, Neville D.; Tulassay, Zsolt; Juhasz, Laszlo; Racz, Istvan; Howard, John M.; van Rensburg, Christoffel J.; Swannell, Anthony J.; Hawkey, Christopher J. A Comparison of Omeprazole with Ranitidine for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs.N Engl J Med 1998;338:719-726.
  2. Wilder-Smith,C; Bondarov,P; Lundgren,M. Intravenous esomeprazole (40 mg and 20 mg) inhibits gastric acid secretion as effectively as oral esomeprazole: results of two randomized clinical studies.European Journal of Gastroenterology & Hepatology. Volume 17(2), February 2005, pp 191-197.
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Therapeutic Class Comparison Articles

  1. Yeomans, Neville D.; Tulassay, Zsolt; Juhasz, Laszlo; Racz, Istvan; Howard, John M.; van Rensburg, Christoffel J.; Swannell, Anthony J.; Hawkey, Christopher J. A Comparison of Omeprazole with Ranitidine for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs.N Engl J Med 1998;338:719-726.
  2. Wilder-Smith,C; Bondarov,P; Lundgren,M. Intravenous esomeprazole (40 mg and 20 mg) inhibits gastric acid secretion as effectively as oral esomeprazole: results of two randomized clinical studies.European Journal of Gastroenterology & Hepatology. Volume 17(2), February 2005, pp 191-197.

Pharmacokinetics Articles

  1. Simon B, Muller P, Pascu O, Gatz G, Sander P, Huber R, et al. Intra-oesophageal pH profiles and pharmacokinetics of pantoprazole and esomeprazole: a crossover study in patients with gastro-oesophageal reflux disease. European Journal of Gastroenterology & Hepatology 2003;15(7):791-9.
  2. Sjövall,H; Björnsson,E; Holmberg,J; Hasselgren,G; Pharmacokinetic study of esomeprazole in patients with hepatic impairment. European Journal of Gastroenterology & Hepatology. Volume 14(5), May 2002, pp 491-496.
  3. Dixit RK, Chawla AB, Kumar N, Garg SK.Effect of omeprazole on the pharmacokinetics of sustained-release carbamazepine in healthy male volunteers.Methods Find Exp Clin Pharmacol. 2001 Jan-Feb;23(1):37-9.
  4. 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.
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Drug Interaction Articles

  1. Hurwitz A, Ruhl CE, Kimler BF, Topp EM, Mayo MS.Gastric function in the elderly: effects on absorption of ketoconazole.J Clin Pharmacol. 2003 Sep;43(9):996-1002.
  2. Dixit RK, Chawla AB, Kumar N, Garg SK.Effect of omeprazole on the pharmacokinetics of sustained-release carbamazepine in healthy male volunteers.Methods Find Exp Clin Pharmacol. 2001 Jan-Feb;23(1):37-9.
  3. 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.
  4. Soll AH, for the Practice Parameters Committee of the American College of Gastroenterology. Medical Treatment of Peptic Ulcer Disease: Practice Guidelines. JAMA 1996;275:622—9.
  5. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994;120:211—5.

Adverse Effects Articles

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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources

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