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.
References
1. AstraZeneca. Nexium (esomeprazole magnesium) delayed-release capsules prescribing information. Wilmington, DE; 2006 Apr.
2. McTavish D, Buckley MM, Heel RC. Omeprazole. An updated review of its pharmacology and therapeutic use in acid-related disorders. Drugs. 1991; 42:138-70. [PubMed 1718683]
3. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders. Drugs. 1998; 56:307-35. [PubMed 9777309]
4. Lindberg P, Brändström A, Björn W et al. Omeprazole: The first proton pump inhibitor. Med Res Rev. 1990; 10:1-54.
5. Thitiphuree S, Talley NJ. Esomeprazole, a new proton pump inhibitor: Pharmacological characteristics and clinical efficacy. Int J Clin Pract. 2000; 54:537-41. [IDIS 456578] [PubMed 11198734]
6. Astra Merck. Prilosec (omeprazole) delayed-release capsules prescribing information. Wayne, PA; 1998 Jun.
7. Massoomi F, Savage J, Destache CJ. Omeprazole: a comprehensive review. Pharmacotherapy. 1993; 13:46- 59. [IDIS 311791] [PubMed 8437967]
8. Howden CW. Clinical pharmacology of omeprazole. Clin Pharmacokinet. 1991; 20:38-49. [PubMed 2029801]
9. Shamburek RD, Schubert ML. Pharmacology of gastric acid inhibition. Balilliere's Clin Gastroenterol. 1993; 7:23-54.
10. Maton PN. Omeprazole. N Engl J Med. 1991; 324:965-75. [IDIS 279274] [PubMed 2002819]
11. Sontag SJ, Hirschowitz BI, Holt S et al. Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: the U.S. multicenter study. Gastroenterology. 1992; 102:109-118. [IDIS 289938] [PubMed 1727744]
12. Eisai Inc. and Janssen Pharmaceutica Inc. AcipHex (rabeprazole sodium) delayed-release tablets prescribing information. Teaneck and Titusville, NJ; 1999 Aug.
13. Prakash A, Faulds D. Rabeprazole. Drugs. 1998; 55:261-7. [PubMed 9506245]
14. Dekkers CP, Beker JA, Thjodleifsson B et al for the European Rabeprazole Study Group. Double-blind comparison (correction of double-blind, placebo-controlled comparison) of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or ulcerative gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 1999; 13:49-57. [PubMed 9892879]
15. National Institutes of Health Consensus Development Group. Gastroesophageal reflux disease (hiatal hernia and heartburn). NIH Publication No. 94-882; 1994 Sep.
16. Cloud ML, Enas N, Humphries TJ et al for the Rabeprazole Study Group. Rabeprazole in treatment of acid peptic diseases: results of three placebo-controlled dose-response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). Dig Dis Sci. 1998; 43:993-1000. [IDIS 406275] [PubMed 9590413]
17. Graul A, Castaner R, Castaner J. Esomeprazole magnesium. Drugs Future. 1999; 24:1178-83.
18. Kahrilas PJ, Falk GW, Johnson DA et al for the Esomeprazole Study Investigators. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: A randomized controlled trial. Aliment Pharmacol Ther. 2000; 14:1249-58. [PubMed 11012468]
19. Spencer CM, Faulds D. Esomeprazole. Drugs. 2000; 60:321-9. [PubMed 10983736]
20. AstraZeneca, Frazer, PA: Personal communication.
21. DeVault KR, Castell DO, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 1999; 94:1434-42. [IDIS 429620] [PubMed 10364004]
22. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults: Practice Guidelines. Am J Gastroenterol. 2001; 96:635-43. [IDIS 461432] [PubMed 11280528]
23. Valori RM, Cockel R. Omeprazole for duodenal ulceration in Crohn's disease. Br Med J. 1990; 300:438-9.
24. Bianchi G, Ardizzone S, Petrillo M et al. Omeprazole for peptic ulcer in Crohn's disease. Am J Gastroenterol. 1991; 86: 245-6. [PubMed 1992643]
25. Przemioslo RT, Mee AS. Omeprazole in possible esophageal Crohn's disease. Dig Dis Sci. 1994; 39:1594-5. [IDIS 333053] [PubMed 8026276]
26. Dickinson JB. Is omeprazole helpful in inflammatory bowel disease? J Clin Gastroenterol. 1994; 18:317-9.
27. Abrahao LJ Jr., Abrahao LJ, Vargas C et al. [Gastoduodenal Crohn's disease—report of 4 cases and review of the literature]. (Portuguese; with English abstract.) Arq Gastroenterol. 2001; 38:57-62.
28. Freston JW. Review article: role of proton pump inhibitors in non-H. pylori-related ulcers. Aliment Pharmacol Ther. 20001; 15(Suppl 2):2-5.
29. Laheij RJF, Sturkenboom MCJM, Hassing RJ et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:1955-60.
30. Gregor JC. Acid suppression and pneumonia.; a clinical indication for rational prescibing. JAMA. 2004;292:2012-3. Editorial.
31. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2009 Apr.
32. Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (Nov 3, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.
33. Scheiman JM, Yeomans ND, Talley NJ et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol. 2006; 101:701-10. [PubMed 16494585]
34. AstraZeneca. Nexium I.V. (esomeprazole sodium) for injection prescribing information. Wilmington, DE; 2005 Aug.
35. Yang Y-X, Lewis JD, Epstein S et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296:2947-53. [PubMed 17190895]
36. Food and Drug Administration. FDA statement: FDA's safety reviews of Prilosec and Nexium find no evidence of increased rates of cardiac events. 2007 Dec 10. From the FDA website. Accessed 2007 Dec 21.
37. Food and Drug Administration. Update of safety review: follow-up to the August 9, 2007, communication about the ongoing safety review of omeprazole and esomeprazole. 2007 Dec 10. From the FDA website. Accessed 2007 Dec 21.
38. Food and Drug Administration. Early communication about an ongoing safety review: omeprazole (Prilosec) and esomeprazole (Nexium). 2007 Aug 9. From the FDA website. Accessed 2007 Dec 21.
39. Metz DC, Sostek MB, Ruszniewski P et al. Effects of esomeprazole on acid output in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion. Am J Gastroenterol. 2007; 102:2648-54. [PubMed 17764495]
40. Gilard M, Arnaud B, Cornily JC et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. JACC. 2008; 51:256-60, doi:10.1016/j.jacc.2007.06.064. Accessed 2008 Dec 8. Available from website. [PubMed 18206732]
41. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC. 2008; 52:1038-9. Letter. [PubMed 18786491]
42. MEDCO. New study: A common class of GI medications reduce protection against heart attack in patients taking widely prescribed cardiovascular drug. Franklin Lakes, NJ; 2008 Nov 11. Press release from website.
43. Gilard M, Cornily JC, Boschat J. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC. 2008; 52:1039. Reply.
44. . PPI interactions with clopidogrel revisited. Med Lett Drugs Ther. 2009; 51:13-4.
45. Juurlink DN, Gomes T, Ko DT et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009; 180:713-8. [PubMed 19176635]
46. Food and Drug Administration. Information on clopidogrel bisulfate (marketed as Plavix). Rockville, MD; 2010 Oct 27. From FDA website.
224. Sanofi-Aventis/Bristol-Myers Squibb. Plavix, (clopidogrel bisulfate) tablets prescribing information. New York, NY; 2010 Mar.
225. Food and Drug Administration. Early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). Rockville, MD; 2009 Jan 26. From FDA website.
226. Siller-Matula JM, Spiel AO, Lang IM et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009; 157:148.e1-5.
227. Gilard M, Arnaud B, Le Gal G et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost. 2006; 4:2508-9. [PubMed 16898956]
228. Anon. PPI interactions with clopidogrel. Med Lett Drugs Ther. 2009; 51:2-3.
229. Aubert RE, Epstein RS, Teagarden JR et al. Proton pump inhibitors effect on clopidogrel effectiveness: The clopidogrel Medco outcomes study. Circulation. 2008; 118:S_815, Abstract 3998.
230. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009; 180:699-700. [PubMed 19332744]
232. Food and Drug Administration. Information for heathcare professionals: Update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert heathcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). Rockville, MD; 2009 Nov 17. From FDA website.
233. Food and Drug Administration. Follow-up to the January 26, 2009 Early Communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed as Prilosec and Prilosec OTC). Rockville, MD; 2009 Nov 17. From FDA website.
235. Ho PM, Maddox TM, Wang L et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009; 301:937-44.
236. Norgard NB, Mathews KD, Wall GC. Drug-drug interaction between clopidogrel and the proton pump inhibitors. Ann Pharmacother. 2009; 43:1266-74. [PubMed 19470853]
237. Last EJ, Sheehan AH. Review of recent evidence: potential interaction between clopidogrel and proton pump inhibitors. Am J Health Syst Pharm. 2009; 66:2117-22. [PubMed 19923312]
238. Stanek EJ, Aubert RE, Flockhart DA et al. A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: the Clopidogrel Medco Outcomes Study. Available from website. Accessed 2009 Dec 15.
240. Stockl KM, Le L, Zakharyan A et al. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med. 2010; 170:704-10. [PubMed 20421557]
243. Juurlink DN. Proton pump inhibitors and clopidogrel: putting the interaction in perspective. Circulation. 2009; 120:2310-2. [PubMed 19933929]
248. Khalique SC, Cheng-Lai A. Drug interaction between clopidogrel and proton pump inhibitors. Cardiol Rev. 2009 Jul-Aug; 17:198-200. [PubMed 19525682]
250. Rude MK, Chey WD. Proton-pump inhibitors, clopidogrel, and cardiovascular adverse events: fact, fiction, or something in between?. Gastroenterology. 2009; 137:1168-71. [PubMed 19635603]
300. Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int. 2006; 79:76-83. [PubMed 16927047]
301. Corley DA, Kubo A, Zhao W et al. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology. 2010; 139:93-101. [PubMed 17190895]
302. Yu EW, Blackwell T, Ensrud KE et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int. 2008; 83:251-9. [PubMed 19931262]
303. Gray SL, LaCroix AZ, Larson J et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Arch Intern Med. 2010; 170:765-71. [PubMed 20458083]
304. Targownik LE, Lix LM, Metge CJ et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008; 179:319-26. [PubMed 18695179]
305. Food and Drug Administration. Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. May 25, 2010. From FDA web site.
