Esomeprazole Sodium

Class: Proton-pump Inhibitors
Note: This monograph also contains information on Esomeprazole Magnesium
VA Class: GA900
Chemical Name: 5-Methoxy-2-[(S)[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole magnesium salt trihydrate
Molecular Formula: C₃₄H₃₆MgN₆O₆S₂•3H₂OC₁₇H₁₈N₃O₃S•Na
CAS Number: 217087-09-7
Brands: Nexium

Special Alerts:

[Posted 03/02/2011] ISSUE: FDA notified healthcare professionals and the public that prescription proton pump inhibitor (PPI) drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time (in most cases, longer than one year). Low serum magnesium levels can result in serious adverse events including muscle spasm (tetany), irregular heartbeat (arrhythmias), and convulsions (seizures); however, patients do not always have these symptoms. Treatment of hypomagnesemia generally requires magnesium supplements. In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.

BACKGROUND: PPIs work by reducing the amount of acid in the stomach and are used to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus.

RECOMMENDATION: Healthcare professionals should consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia. For patients taking digoxin, a heart medicine, this is especially important because low magnesium can increase the likelihood of serious side effects. Healthcare professionals should consider obtaining magnesium levels periodically in these patients. For additional information, refer to the Data Summary section of the FDA Drug Safety Communication. For more information visit the FDA website at: and .

[Posted 05/25/2010] FDA notified healthcare professionals and patients of revisions to the prescription and over-the-counter [OTC] labels for proton pump inhibitors, which work by reducing the amount of acid in the stomach, to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.

The new safety information is based on FDA's review of several epidemiological studies that found those at greatest risk for these fractures received high doses of proton pump inhibitors or used them for one year or more. The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture primarily was observed in this age group. While the greatest increased risk for fractures in these studies involved people who had been taking prescription proton pump inhibitors for at least one year or who had been taking high doses of the prescription medications (not available over-the-counter), as a precaution, the “Drug Facts” label on the OTC proton pump inhibitors (indicated for 14 days of continuous use) also is being revised to include information about this risk. FDA recommends healthcare professionals, when prescribing proton pump inhibitors, should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.

The safety communication includes a data summary with a table and references which support the epidemiological studies reviewed for this communication. For more information visit the FDA website at: and .

Introduction

Acid- or proton-pump inhibitor; gastric antisecretory agent.^{1 3 5 19 34} S-isomer of omeprazole.^{1 5 9 34}

Uses for Esomeprazole Sodium

Gastroesophageal Reflux (GERD)

Short-term treatment of symptomatic GERD (e.g., heartburn) in patients without erosive esophagitis.¹

Short-term treatment of erosive esophagitis (diagnostically confirmed) in patients with GERD.¹

Maintain healing, symptom resolution, and decrease recurrence of erosive esophagitis.¹

IV as short-term (≤10 days) alternative to oral therapy in patients with a history of erosive esophagitis who are unable to continue taking the drug orally.³⁴

Duodenal Ulcer

Treatment of Helicobacter pylori infection and duodenal ulcer disease (active duodenal ulcer or history of duodenal ulcer in the past 5 years).¹ Used in conjunction with amoxicillin and clarithromycin (triple therapy).¹

NSAIA-associated Ulcers

Reduction in the occurrence of gastric ulcers associated with chronic NSAIA therapy in patients at risk (i.e., ≥60 years of age and/or history of gastric ulcer).^{1 33} Effect on occurrence of duodenal ulcers not established.^{1 33}

Crohn's Disease-associated Ulcers

Some evidence for use of proton-pump inhibitors (e.g., omeprazole) for gastric acid suppressive therapy as an adjunct in the management of upper GI Crohn's disease†, including esophageal, gastroduodenal, and jejunoileal disease.^{22 23 24 25 26 27 28}

Esomeprazole Sodium Dosage and Administration

Administration

Oral Administration

Administer orally at least 1 hour before a meal.¹

Antacids may be used concomitantly as needed for pain relief.¹

Capsules

Swallow capsules intact; do not chew or crush.¹

Alternatively, open capsule and mix contents with 1 tablespoon applesauce; swallow immediately without chewing.¹ Applesauce should not be hot and should be soft enough to swallow without chewing.¹

NG Tube

Open capsule, empty intact granules into 60-mL syringe, and mix with 50 mL of water.¹ Replace plunger and shake well for 15 seconds.¹ Hold syringe with tip upright and check tip for remaining granules.¹ Administer immediately through NG tube; flush with additional water.¹ Do not administer if pellets have dissolved or disintegrated.¹

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by slow direct IV injection or by IV infusion.³⁴

Flush the IV line with 0.9% sodium chloride, lactated Ringer's, or 5% dextrose injection before and after administration.³⁴

Do not administer with any other drugs or diluents because of potential incompatibilities.³⁴

Reconstitution

For direct IV injection, reconstitute vial containing 20 or 40 mg of esomeprazole with 5 mL of 0.9% sodium chloride injection.³⁴

For IV infusion, reconstitute vial containing 20 or 40 mg of esomeprazole with 5 mL of 5% dextrose, 0.9% sodium chloride, or lactated Ringer's injection.³⁴ Dilute reconstituted solution prior to infusion.³⁴

Dilution

For IV infusion, dilute the reconstituted solution to a final volume of 50 mL with a compatible IV solution (see Compatibility under Stability).³⁴

Rate of Administration

Administer reconstituted solution by slow (over ≥3 minutes) direct IV injection.³⁴

Administer diluted solution by IV infusion over 10–30 minutes.³⁴

Dosage

Available as esomeprazole magnesium and esomeprazole sodium; dosage expressed in terms of esomeprazole.^{1 34}

Pediatric Patients

GERD

Oral

Adolescents 12–17 years of age: 20 or 40 mg once daily for up to 8 weeks.¹

Adults

GERD

GERD Without Erosive Esophagitis

Oral

20 mg once daily for 4 weeks; may give an additional 4 weeks of therapy.¹ Chronic proton-pump inhibitor therapy may be appropriate.²¹

Treatment of Erosive Esophagitis

Oral

20 or 40 mg once daily for 4–8 weeks;¹ may give an additional 4–8 weeks of therapy.¹

IV

20 or 40 mg once daily for up to 10 days.³⁴ Discontinue IV administration as soon as patient can resume oral esomeprazole therapy.³⁴

Maintenance of Healing of Erosive Esophagitis

Oral

20 mg once daily; not studied >6 months.¹

Duodenal Ulcer

Helicobacter pylori Infection and Duodenal Ulcer

Oral

Triple therapy: 40 mg once daily for 10 days in conjunction with amoxicillin and clarithromycin.¹

NSAIA-associated Ulcers

Prevention of Gastric Ulcers

Oral

20 or 40 mg once daily; not studied >6 months.¹

Special Populations

Hepatic Impairment

Oral or IV dosage should not exceed 20 mg once daily in patients with severe (Child-Pugh class C) hepatic impairment.^{1 34} No dosage adjustment required for mild or moderate (Child-Pugh class A or B, respectively) hepatic impairment.^{1 34}

Cautions for Esomeprazole Sodium

Contraindications

• 
  

  Known hypersensitivity to esomeprazole, any ingredient in the formulation, or other substituted benzimidazoles (e.g., lansoprazole, omeprazole, pantoprazole, rabeprazole).^{1 34}

  
  

Warnings/Precautions

General Precautions

GI Effects

Response to esomeprazole does not preclude presence of occult gastric neoplasm.^{1 34} Atrophic gastritis reported occasionally with long-term omeprazole use.^{1 34}

Respiratory Effects

Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).^{29 30}

Hip Fracture

Several observational studies suggest that use of proton-pump inhibitors, particularly in high dosages (i.e., multiple daily doses) and/or for prolonged periods of time (i.e., ≥1 year), may be associated with increased risk of osteoporosis-related fractures of the hip, wrist, or spine.^{35 300 301 302 303 304 305 309} Magnitude of risk is unclear;^{35 300 301 302 303 304 305 310} causality not established.³⁰⁵ FDA is continuing to evaluate this safety concern.³⁰⁵

Use the lowest effective dosage and shortest duration of therapy appropriate for the patient's clinical condition.^{35 301 303 305 307 309}

Individuals at risk for osteoporosis-related fractures should receive an adequate intake of calcium and vitamin D; assess and manage these patients' bone health according to current standards of care.^{35 303 305 307 309}

Cardiovascular Effects

Preliminary safety data from 2 long-term clinical trials comparing esomeprazole or omeprazole with antireflux surgery in patients with severe GERD raised concerns about a potential increased risk of cardiac events (e.g., MI, heart failure, sudden death) in patients receiving these drugs.^{36 37 38} After reviewing data from these and other studies, FDA has concluded that long-term use of these drugs is not likely to be associated with an increased risk of such cardiac events.^{36 37 38} FDA recommends that clinicians continue to prescribe and patients continue to use these drugs in the manner described in the manufacturers' labelings.^{36 37 38}

Specific Populations

Pregnancy

Category B.^{1 34}

Lactation

Not known whether esomeprazole is distributed into milk, but omeprazole is distributed into milk.^{1 34} Discontinue nursing or the drug.^{1 34}

Pediatric Use

Safety and efficacy of oral esomeprazole for short-term treatment of GERD in adolescents 12–17 years of age is supported by controlled clinical trials in adults and safety and pharmacokinetic studies in adolescents.¹ Adverse effects and pharmacokinetics similar in adolescents and adults.¹

Safety and efficacy of oral esomeprazole for short-term treatment of GERD in children <12 years of age or for other uses in pediatric patients not established.¹

Safety and efficacy of IV esomeprazole in pediatric patients not established.³⁴

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.^{1 34}

Hepatic Impairment

Use with caution.^{1 20} (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, dizziness, diarrhea, nausea, flatulence, dyspepsia, abdominal pain, constipation, dry mouth.^{1 19 34}

Interactions for Esomeprazole Sodium

Extensively metabolized by CYP isoenzymes, principally CYP2C19; also to lesser extent by CYP3A4.^{1 19 34} May inhibit CYP2C19; unlikely to inhibit CYP3A4, 1A2, 2A6, 2C9, 2D6, or 2E1.^{1 34}

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential to inhibit metabolism of drugs metabolized by CYP2C19.^{1 34} Interaction unlikely with drugs metabolized by other CYP isoenzymes.^{1 34}

Specific Drugs

Drug	Interaction	Comments
Amoxicillin	Pharmacokinetic interaction unlikely1 34
Atazanavir	Possible altered oral absorption of atazanavir, resulting in decreased plasma atazanavir concentrations; possible loss of virologic response1 31	Manufacturer of esomeprazole states that concomitant administration with atazanavir is not recommended1 Antiretroviral treatment-naive patients: If a proton-pump inhibitor is used concomitantly with atazanavir, administer ritonavir-boosted atazanavir (atazanavir 300 mg and ritonavir 100 mg once daily with food); administer the proton-pump inhibitor approximately 12 hours before ritonavir-boosted atazanavir31 32 For treatment-naive patients, dosage of proton-pump inhibitor should not exceed omeprazole 20 mg daily (or equivalent)31 32 Antiretroviral treatment-experienced patients: Concomitant use of proton-pump inhibitors with atazanavir not recommended31 32
Clarithromycin	Increased plasma concentrations of esomeprazole and 14-hydroxyclarithromycin 1	Not considered clinically important1 34 316
Clopidogrel	Certain CYP2C19 inhibitors (e.g., omeprazole) reduce exposure to clopidogrel's active metabolite and decrease platelet inhibitory effects; potentially may reduce clopidogrel's clinical efficacy.44 224 225 228 232 233 236 311 Extent to which other proton-pump inhibitors (which may differ in CYP2C19-inhibitory potency) may interfere with clopidogrel's effects is unknown40 41 42 46 224 232	Assess risks and benefits of concomitant proton-pump inhibitor and clopidogrel use in individual patients312 313 314 315 316 American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that GI bleeding risk reduction with concomitant proton-pump inhibitor in patients with risk factors for GI bleeding (e.g., advanced age; concomitant use of warfarin, corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIAs); H. pylori infection) may outweigh potential reduction in cardiovascular efficacy of antiplatelet treatment associated with a drug–drug interaction.311 In patients without such risk factors, ACCF/ACG/AHA states that risk/benefit balance may favor use of antiplatelet therapy without a proton-pump inhibitor.311
Diazepam	Decreased diazepam metabolism and increased plasma concentrations1 34	Not considered clinically important1 34
Gastric pH-dependent drugs (e.g., digoxin, iron salts, ketoconazole)	Esomeprazole may decrease drug absorption1 34
NSAIAs (naproxen, rofecoxib)	Pharmacokinetic interaction unlikely1 34
Oral contraceptives	No change in esomeprazole pharmacokinetics1 34
Phenytoin	Pharmacokinetic interaction unlikely1 34
Quinidine	Pharmacokinetic interaction unlikely1 34
Sucralfate	Possible delayed proton-pump inhibitor absorption and decreased bioavailability c	Administer proton-pump inhibitor at least 30 minutes before sucralfatec
Warfarin	Potential for decreased warfarin metabolism and changes in prothrombin measures1 34	Monitor PT and INR1 34

Esomeprazole Sodium Pharmacokinetics

Absorption

Bioavailability

Bioavailability is 64% after a single 40-mg oral dose.¹ Bioavailability is 90% after repeated oral doses of 40 mg once daily.¹

Food

AUC decreased by 43–53% when a 40-mg oral dose was administered with food.¹

Special Populations

Following oral dosage of 40 mg once daily in patients with severe (Child-Pugh class C) hepatic impairment, steady-state AUCs were 2–3 times greater than those in patients with normal hepatic function.^{1 34}

Distribution

Extent

Not known whether esomeprazole is distributed into milk, but omeprazole is distributed into milk.^{1 34} Not known whether esomeprazole crosses the placenta.^{1 34}

Prolonged binding to gastric parietal proton pump enzyme.^{1 6}

Plasma Protein Binding

97%.^{1 34}

Elimination

Metabolism

Metabolized to inactive metabolites in the liver by CYP isoenzymes, principally by CYP2C19, and to lesser extent by CYP3A4.^{1 34}

Elimination Route

Excreted principally in urine (80% as inactive metabolites, <1% as active drug); remainder in feces as inactive metabolites.^{1 34}

Half-life

Adults, oral administration: 1–1.5 hours.¹ Slower elimination than R-omeprazole or racemic omeprazole (0.5–1 hour).^{1 5 6}

Adults, IV administration: 1.1–1.4 hours; prolonged with increasing dose.³⁴

Adolescents 12–17 years of age, oral administration: 0.8–1.2 hours.¹

Special Populations

In patients with poor CYP2C19 metabolizer phenotype, steady-state AUCs were 2 times greater than those in patients with extensive (or rapid) metabolizer phenotype.^{1 34}

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C) in tightly-closed containers.¹

Parenteral

Powder for IV Injection or Infusion

Powder: 25°C (may be exposed to 15–30°C).³⁴ Protect from light.³⁴

Reconstituted solution: Room temperature (up to 30°C) for up to 12 hours.³⁴

Admixture: Room temperature (up to 30°C) for up to 6 hours (in 50 mL of 5% dextrose injection) or 12 hours (in 50 mL of lactated Ringer's or 0.9% sodium chloride injection).³⁴

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Oral

Capsules

Use extemporaneous mixture of capsule contents (enteric-coated pellets) and applesauce immediately; do not store for future use.¹ Applesauce should not be hot.¹

Parenteral

Solution Compatibility³⁴

Compatible
Dextrose 5% in water
Ringer's injection, lactated
Sodium chloride 0.9%

Actions

• 
  

  Inhibits basal and stimulated gastric acid secretion.^{1 2 7 8 9}

  
  


• 
  

  Concentrates in acid conditions of parietal cell secretory canaliculi; forms active sulfenamide metabolite that irreversibly binds to and inactivates hydrogen-potassium ATPase (proton- or acid pump), blocking final step in secretion of hydrochloric acid.^{1 2 4 7 8 9 10 34} Acid secretion is inhibited until additional hydrogen-potassium ATPase is synthesized, resulting in prolonged duration of action.^{2 4 7 8 9 10}

  
  


• 
  

  More esomeprazole reaches and blocks proton pump than does R-omeprazole; therefore, provides greater intragastric pH control than racemic omeprazole.^{1 5}

  
  


• 
  

  Suppresses H. pylori in patients with duodenal ulcer and/or reflux esophagitis who are infected with the organism.² Combined therapy with esomeprazole and appropriate anti-infectives (i.e., amoxicillin, clarithromycin) can effectively eradicate H. pylori gastric infection.^{1 2}

  
  

Advice to Patients

• 
  

  Importance of swallowing capsule intact, without crushing or chewing.¹

  
  


• 
  

  Importance of taking 1 hour before a meal.¹

  
  


• 
  

  If mixed with applesauce for administration, importance of mixing capsule contents with applesauce soft enough to swallow without chewing.¹ Importance of not using hot applesauce.¹ Importance of immediately swallowing mixture without crushing or chewing;¹ do not store for later use.¹

  
  


• 
  

  Importance of advising patients that use of multiple daily doses of the drug for an extended period of time may increase the risk of fractures of the hip, wrist, or spine.^{305 309}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹ Antacids may be used concomitantly as needed for pain relief.¹

  
  


• 
  

  Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 34}

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Esomeprazole Magnesium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, delayed-release (containing enteric-coated pellets)	20 mg (of esomeprazole)	Nexium	AstraZeneca
		40 mg (of esomeprazole)	Nexium	AstraZeneca

Esomeprazole Sodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use	20 mg (of esomeprazole)	Nexium I.V.	AstraZeneca
		40 mg (of esomeprazole)	Nexium I.V.	AstraZeneca

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

NexIUM 20MG Delayed-release Capsules (ASTRAZENECA LP): 30/$200.99 or 90/$547.96

NexIUM 40MG Delayed-release Capsules (ASTRAZENECA LP): 30/$182.99 or 90/$524.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions March 24, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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