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Special Alerts
Clopidogrel (Plavix®) and Proton Pump Inhibitors (PPIs): Health Canada Issues Notice- August 2009
Health Canada, in conjunction with Sanofi-Aventis Canada Inc., and Bristol Myers Squibb Canada Co., has issued a Dear HealthCare Professional letter to Canadian practitioners regarding the potential interaction between clopidogrel (Plavix®) and proton pump inhibitors (PPIs). A similar notice had previously been issued in the U.S. by the Food and Drug Administration (FDA). Certain PPIs may inhibit the cytochrome enzyme (CYP2C19) which metabolizes clopidogrel to its active metabolite, thus potentially resulting in decreased clinical efficacy of clopidogrel.
Health Canada is recommending that healthcare providers continue to prescribe clopidogrel and patients continue taking clopidogrel as directed. Health Canada recommends against the use of drugs (including PPIs) which inhibit CYP2C19 in patients receiving clopidogrel. Prescribers should consider the risk-benefits of combination (PPI-clopidogrel) therapy as well as use of alternative gastroprotective agents. Health Canada is currently working with the manufacturers mentioned to update the Canadian product monograph with this important safety information.
Further information may be found at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/plavix_hpc-cps-eng.php
Clopidogrel (Plavix®) and Proton Pump Inhibitors (PPIs): Ongoing Safety Review - January 2009; Updated June 2009
The U.S. Food and Drug Administration (FDA) is communicating important information regarding an ongoing safety review of clopidogrel and its effectiveness when used with proton pump inhibitors (PPIs).
Clopidogrel is a prodrug requiring hepatic conversion via CYP3A4 and/or CYP2C19 to its active metabolite. Impaired clopidogrel conversion to its active metabolite may be due to either CYP450 polymorphisms or drug-drug interactions resulting in suboptimal antiplatelet activity.
A PPI is often prescribed with the combination of aspirin and clopidogrel to prevent gastrointestinal bleeding. A number of PPIs are available and include dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. Several studies have reported greater clinical event rates (eg, myocardial infarction, death) or greater platelet reactivity associated with concurrent use of clopidogrel and a PPI (Ho, 2008; Pezella, 2008; Gilard, 2006). Similarly, a prospective, randomized, double-blind trial demonstrated a reduction in antiplatelet activity when omeprazole and clopidogrel are used concurrently (Gilard, 2008). Another controlled trial with the PPI lansoprazole also found evidence of a possible interaction resulting in less antiplatelet activity (Small, 2008). This interaction is thought to result from competitive inhibition of the CYP2C19-mediated activation of clopidogrel by omeprazole and other PPIs, which are all metabolized to at least some degree by CYP2C19. In contrast, one study with esomeprazole and pantoprazole did not find evidence of reduced antiplatelet activity when administered with clopidogrel (Siller-Matula, 2009), highlighting the need for additional studies to determine the degree to which individual PPIs may differ in their potential for interacting with clopidogrel.
The manufacturer of Plavix® has agreed to conduct further studies to better understand the effect of other drugs (including PPIs) and genetic factors on the effectiveness of clopidogrel. The FDA is recommending that healthcare providers continue to prescribe clopidogrel while reevaluating the need for prescription or over-the-counter (OTC) PPIs in patients taking clopidogrel. Patients should continue taking clopidogrel as directed. If taking a PPI with clopidogrel, patients should consult with their healthcare provider.
More recently, the Clopidogrel Medco Outcomes Study (Stanek, 2009) was presented at the Society for Cardiovascular Angiography and Interventions (SCAI) Annual Scientific Sessions. The study was a retrospective cohort analysis evaluating integrated medical and pharmacy claims. Patients included (n=16,718) were those who had a coronary stent procedure with a new clopidogrel prescription claim within 1 month of procedure. Patients were segregated according to PPI use; newer PPIs (ie, rabeprazole, dexlansoprazole) were not included in the analysis. Those who received a PPI demonstrated a 51% increase in the risk of cardiovascular events (MI, unstable angina, stroke, repeat coronary procedure) compared to those who did not receive a PPI (lansoprazole 24.3%; pantoprazole 29.2%; esomeprazole 24.9%; omeprazole 25.1% vs 17.9%). SCAI has urged healthcare providers to consider prescribing alternatives to PPI use, such as an antacid or H2 blocker (eg, famotidine, ranitidine, or cimetidine). Of note, cimetidine is a moderate CYP2C19 inhibitor. Although no documented interactions exist, theoretically cimetidine may also reduce conversion of clopidogrel to its active metabolite. In cases where gastrointestinal conditions require treatment, the patient's primary care provider or gastroenterologist should be contacted to discuss treatment options.
For more information, healthcare professionals may refer to the following websites:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079520.htm
http://www.scai.org/drlt1.aspx?PAGE_ID=5870
References:
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(9):937-44.
Pezalla E, Day D, and Pulliadath I, “Initial Assessment of Clinical Impact of a Drug Interaction Between Clopidogrel and Proton Pump Inhibitors,” J Am Coll Cardiol, 2008, 52(12):1038-9.
Gilard M, Arnaud B, Le Gal G, et al, “Influence of Omeprazol on the Antiplatelet Action of Clopidogrel Associated to Aspirin,” J Thromb Haemost, 2006, 4(11):2508-9.
Gilard M, Arnaud B, Cornily JC, et al, “Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated With Aspirin: The Randomized, Double-Blind Ocla (Omeprazole Clopidogrel Aspirin) Study,” J Am Coll Cardiol, 2008, 51(3):256-60.
Siller-Matula JM, Spiel AO, Lang IM, et al, “Effects of Pantoprazole and Esomeprazole on Platelet Inhibition by Clopidogrel,” Am Heart J, 2009, 157(1):148.e1-5.
Small DS, Farid NA, Payne CD, et al, “Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel,” J Clin Pharmacol, 2008, 48(4):475-84.
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,” Society for Cardiovascular Angiography and Interventions 2009 Scientific Sessions; May 6, 2009; Las Vegas, NV.
Medication Safety Issues
Sound-alike/look-alike issues:
Esomeprazole may be confused with aripiprazole
Nexium® may be confused with Nexavar®
Pronunciation
(es oh ME pray zol)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Oral: Short-term (4-8 weeks) treatment of erosive esophagitis; maintaining symptom resolution and healing of erosive esophagitis; treatment of symptomatic gastroesophageal reflux disease (GERD); as part of a multidrug regimen for Helicobacter pylori eradication in patients with duodenal ulcer disease (active or history of within the past 5 years); prevention of gastric ulcers in patients at risk (age ?60 years and/or history of gastric ulcer) associated with continuous NSAID therapy; long-term treatment of pathological hypersecretory conditions including Zollinger-Ellison syndrome
Canadian labeling: Additional use (not in U.S. labeling): Oral: Treatment of nonerosive reflux disease (NERD)
I.V.: Short-term (?10 days) treatment of gastroesophageal reflux disease (GERD) when oral therapy is not possible or appropriate
Use: Unlabeled/Investigational
I.V.: Prevention of recurrent peptic ulcer bleeding postendoscopy
Pregnancy Risk Factor
B
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. However, there are no adequate and well-controlled studies in pregnant women. Congenital abnormalities have been reported sporadically following omeprazole use during pregnancy.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Esomeprazole excretion into breast milk has not been studied. However, omeprazole is excreted in breast milk, and therefore considered likely that esomeprazole is similarly excreted; breast-feeding is not recommended.
Contraindications
Hypersensitivity to esomeprazole, substituted benzimidazoles (ie, lansoprazole, omeprazole, pantoprazole, rabeprazole), or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Atrophic gastritis: Long-term omeprazole therapy has caused atrophic gastritis (by biopsy); this may also occur with esomeprazole.
• Carcinoma: No reports of enterochromaffin-like (ECL) cell carcinoids, dysplasia, or neoplasia have occurred.
Disease-related concerns:
• Gastric malignancy: Relief of symptoms does not preclude the presence of a gastric malignancy.
• Gastrointestinal infection (eg, Salmonella, Campylobacter): Use of proton pump inhibitors may increase risk of these infections.
• Hepatic impairment: Patients with severe liver dysfunction may require dosage reductions.
Dosage form specific issues:
• Intravenous: Safety and efficacy of I.V. treatment beyond 10 days have not been established; transition from I.V. to oral therapy as soon possible.
Other warnings/precautions:
• Appropriate use: Helicobacter pylori eradication: Short-term combination therapy (?7 days) has been associated with a higher incidence of treatment failure. The American College of Gastroenterology recommends 10-14 days of therapy (triple or quadruple) for eradication of H. pylori (Chey, 2007).
Adverse Reactions
Unless otherwise specified, percentages represent adverse reactions identified in clinical trials evaluating the oral formulation.
>10%: Central nervous system: Headache (I.V. 11%; oral ?8%)
1% to 10%:
Cardiovascular: Hypertension (?3%), chest pain (>1%)
Central nervous system: Pain (4%), dizziness (oral >1%; I.V. 3%), anxiety (2%), insomnia (2%), pyrexia (2%), fatigue (>1%)
Dermatologic: Rash (>1%), pruritus (I.V. ?1%)
Endocrine & metabolic: Hypercholesterolemia (2%)
Gastrointestinal: Flatulence (oral ?5%; I.V. 10%), diarrhea (oral ?7%; I.V. 4%), abdominal pain (oral ?6%; I.V. 6% ), nausea (oral 5%; I.V. 6%), dyspepsia (oral > 1%; I.V. 6%), gastritis (?6%), constipation (oral 2%; I.V. 3%), vomiting (?3%), benign GI neoplasm (>1%), dyspepsia (>1%), duodenitis (>1%), epigastric pain (>1%), esophageal disorder (>1%), gastroenteritis (>1%), GI mucosal discoloration (>1%), serum gastrin increased (>1%), tooth disorder (>1%), xerostomia (1%)
Genitourinary: Urinary tract infection (4%)
Hematologic: Anemia (>1%)
Hepatic: Transaminases increased (>1%)
Local: Injection site reaction (I.V. 2%)
Neuromuscular & skeletal: Arthralgia (3%), back pain (>1%), fracture (>1%), arthropathy (1%), myalgia (1%)
Respiratory: Respiratory infection (oral ?9%; I.V. 1%), bronchitis (4%), sinusitis (oral ?4%; I.V. 2%), coughing (>1%), rhinitis (>1%), dyspnea (1%)
Miscellaneous: Accident/injury (?8%), viral infection (4%), allergy (2%), ear infection (2%), hernia (>1%), flu-like syndrome (1%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Abdominal rigidity, aggression, agitation, agranulocytosis, albuminuria, alkaline phosphatase increased, alopecia, anaphylactic reaction/shock, angioedema, anorexia, arthritis exacerbation, asthma exacerbation, benign polyps/nodules, bilirubinemia, blurred vision, bronchospasm, candidiasis (GI and genital), carcinoid tumor of stomach, cervical lymphadenopathy, conjunctivitis, cramps, creatinine increased, cystitis, dehydration, depression, dermatitis, dysmenorrhea, dysphagia, dysuria, edema (including facial, peripheral and tongue), epigastric pain, epistaxis, erythema multiforme, esophageal varices, fibromyalgia syndrome, flushing, fungal infection, gastric retention, GI dysplasia, glycosuria, goiter, gynecomastia, hallucinations, hematuria, hepatic encephalopathy, hepatic failure, hepatitis, hyperhidrosis, hyperparathyroidism, hypertonia, hyperuricemia, hypoesthesia, hypokalemia, hypomagnesemia, hyponatremia, impotence, infusion site reaction (eg, erythema, edema), interstitial nephritis, jaundice, larynx edema, leukocytosis, leukopenia, malaise, micturition increased, migraine, muscular weakness, nervousness, osteoporosis, otitis media, pancreatitis, pancytopenia, paresthesia, pharyngolaryngeal pain, pharyngitis, phlebitis, photosensitivity, polymyalgia rheumatica, polyuria, proteinuria, pruritus ani, rhinorrhea, rigors, sleep disorder, somnolence, Stevens-Johnson syndrome, stomatitis, tachycardia, taste disturbances, thrombocytopenia, thrombophlebitis, thyroid-stimulating hormone increased, tinnitus, total bilirubin increased, toxic epidermal necrolysis, tremor, urticaria, vaginitis, vertigo, vitamin B12 deficiency, weight changes
Metabolism/Transport Effects
Substrate of CYP2C19 (major), 3A4 (major); Inhibits CYP2C19 (moderate)
Drug Interactions
Atazanavir: Proton Pump Inhibitors may decrease the absorption of Atazanavir. Risk D: Consider therapy modification
Benzodiazepines (metabolized by oxidation): Proton Pump Inhibitors may increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Clopidogrel: Proton Pump Inhibitors may diminish the therapeutic effect of Clopidogrel. This appears to be due to reduced formation of the active clopidogrel metabolite. Management: Due to the risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
Dabigatran Etexilate: Proton Pump Inhibitors may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Dasatinib: Proton Pump Inhibitors may decrease the absorption of Dasatinib. Risk D: Consider therapy modification
Delavirdine: Proton Pump Inhibitors may decrease the serum concentration of Delavirdine. Management: Chronic therapy with proton pump inhibitors (PPIs) should be avoided in patients treated with delavirdine. The clinical significance of short-term PPI therapy with delavirdine is uncertain, but such therapy should be undertaken with caution. Risk X: Avoid combination
Erlotinib: Proton Pump Inhibitors may decrease the serum concentration of Erlotinib. Risk X: Avoid combination
Fluconazole: May increase the serum concentration of Proton Pump Inhibitors. Risk C: Monitor therapy
Indinavir: Proton Pump Inhibitors may decrease the serum concentration of Indinavir. Risk C: Monitor therapy
Iron Salts: Proton Pump Inhibitors may decrease the absorption of Iron Salts. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk C: Monitor therapy
Itraconazole: Proton Pump Inhibitors may decrease the serum concentration of Itraconazole. Risk D: Consider therapy modification
Ketoconazole: Proton Pump Inhibitors may decrease the serum concentration of Ketoconazole. Ketoconazole may increase the serum concentration of Proton Pump Inhibitors. Risk D: Consider therapy modification
Mesalamine: Proton Pump Inhibitors may diminish the therapeutic effect of Mesalamine. Proton pump inhibitor-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Consider avoiding concurrent administration of high-dose proton pump inhibitors (PPIs) with sustained-release mesalamine products. Risk D: Consider therapy modification
Methotrexate: Proton Pump Inhibitors may decrease the excretion of Methotrexate. Antirheumatic doses of methotrexate probably hold minimal risk. Risk C: Monitor therapy
Mycophenolate: Proton Pump Inhibitors may decrease the serum concentration of Mycophenolate. Specifically, concentrations of the active mycophenolic acid may be reduced. Risk C: Monitor therapy
Nelfinavir: Proton Pump Inhibitors may decrease serum concentrations of the active metabolite(s) of Nelfinavir. Proton Pump Inhibitors may decrease the serum concentration of Nelfinavir. Risk X: Avoid combination
Posaconazole: Proton Pump Inhibitors may decrease the serum concentration of Posaconazole. Risk X: Avoid combination
Raltegravir: Proton Pump Inhibitors may increase the serum concentration of Raltegravir. Risk C: Monitor therapy
Saquinavir: Proton Pump Inhibitors may increase the serum concentration of Saquinavir. Risk C: Monitor therapy
Tacrolimus: Proton Pump Inhibitors may increase the serum concentration of Tacrolimus. Management: Tacrolimus dose adjustment may be required. Rabeprazole, pantoprazole, or selected H2-receptor antagonists (i.e., ranitidine or famotidine) may be less likely to interact. Genetic testing may predict patients at highest risk. Risk D: Consider therapy modification
Tipranavir: May decrease the serum concentration of Proton Pump Inhibitors. These data are derived from studies with Ritonavir-boosted Tipranavir. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Esomeprazole may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Voriconazole: Proton Pump Inhibitors may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Absorption is decreased by 43% to 53% when taken with food.
Storage
Capsule, granules: Store at 15°C to 30°C (59°F to 86°F). Keep container tightly closed.
Powder for injection: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Per the manufacturer, following reconstitution, solution for injection prepared in NS, and solution for infusion prepared in NS or LR should be used within 12 hours. Following reconstitution, solution for infusion prepared in D5W should be used within 6 hours. Refrigeration is not required following reconstitution.
Additional stability data: Following reconstitution, solutions for infusion prepared in D5W, NS, or LR in PVC bags are chemically and physically stable for 48 hours at room temperature (25°C) and for at least 120 hours under refrigeration (4°C) (Kupiec, 2008).
Reconstitution
Powder for injection:
For I.V. injection: Reconstitute powder with 5 mL NS.
For I.V. infusion: Initially reconstitute powder with 5 mL of NS, LR, or D5W, then further dilute to a final volume of 50 mL.
Mechanism of Action
Proton pump inhibitor suppresses gastric acid secretion by inhibition of the H+/K+-ATPase in the gastric parietal cell
Pharmacodynamics/Kinetics
Distribution: Vdss: 16 L
Protein binding: 97%
Metabolism: Hepatic via CYP2C19 and 3A4 enzymes to hydroxy, desmethyl, and sulfone metabolites (all inactive)
Bioavailability: Oral: 90% with repeat dosing
Half-life elimination: ~1-1.5 hours
Time to peak: Oral: 1.5-2 hours
Excretion: Urine (80%, primarily as inactive metabolites; <1% as active drug); feces (20%)
Dosage
Children 1-11 years: Oral: Note: Safety and efficacy of doses >1 mg/kg/day and/or therapy beyond 8 weeks have not been established.
Symptomatic GERD: 10 mg once daily for up to 8 weeks
Erosive esophagitis (healing):
<20 kg: 10 mg once daily for 8 weeks
?20 kg: 10-20 mg once daily for 8 weeks
Nonerosive reflux disease (NERD) (Canadian labeling): 10 mg once daily for up to 8 weeks
Adolescents 12-17 years: Oral:
GERD: 20-40 mg once daily for up to 8 weeks
NERD (Canadian labeling): 20 mg once daily for 2-4 weeks; lack of symptom control after 4 weeks warrants further evaluation
Adults:
Oral:
Erosive esophagitis (healing): Initial: 20-40 mg once daily for 4-8 weeks; if incomplete healing, may continue for an additional 4-8 weeks; maintenance: 20 mg once daily (controlled studies did not extend beyond 6 months)
NERD (Canadian labeling): Initial: 20 mg once daily for 2-4 weeks; lack of symptom control after 4 weeks warrants further evaluation; maintenance (in patients with successful initial therapy): 20 mg once daily as needed
Symptomatic GERD: 20 mg once daily for 4 weeks; may continue an additional 4 weeks if symptoms persist
Helicobacter pylori eradication:
Manufacturer labeling: 40 mg once daily administered with amoxicillin 1000 mg and clarithromycin 500 mg twice daily for 10 days
American College of Gastroenterology guidelines (Chey, 2007):
Nonpenicillin allergy: 40 mg once daily administered with amoxicillin 1000 mg and clarithromycin 500 mg twice daily for 10-14 days
Penicillin allergy: 40 mg once daily administered with clarithromycin 500 mg and metronidazole 500 mg twice daily for 10-14 days or 40 mg once daily administered with bismuth subsalicylate 525 mg and metronidazole 250 mg plus tetracycline 500 mg 4 times/day for 10-14 days
Canadian labeling: 20 mg twice daily for 7 days; requires combination therapy
Prevention of NSAID-induced gastric ulcers: 20-40 mg once daily for up to 6 months
Treatment of NSAID-induced gastric ulcers (Canadian labeling): 20 mg once daily for 4-8 weeks.
Pathological hypersecretory conditions (Zollinger-Ellison syndrome): 40 mg twice daily; adjust regimen to individual patient needs; doses up to 240 mg/day have been administered
I.V.:
Prevention of recurrent peptic ulcer bleeding postendoscopy (unlabeled use; Sung, 2009): I.V.: 80 mg over 30 minutes, followed by 8 mg/hour infusion for 72 hours, then 40 mg orally once daily for 27 additional days
Treatment of GERD (short-term): 20 mg or 40 mg once daily for ?10 days; change to oral therapy as soon as appropriate
Elderly: No dosage adjustment needed.
Dosage adjustment in renal impairment: No dosage adjustment needed
Dosage adjustment in hepatic impairment:
Safety and efficacy not established in children with hepatic impairment.
Mild-to-moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment needed
Severe hepatic impairment (Child-Pugh class C): Dose should not exceed 20 mg/day
Administration: Oral
Capsule: Should be swallowed whole and taken at least 1 hour before eating (best if taken before breakfast). Capsule can be opened and contents mixed with 1 tablespoon of applesauce. Swallow immediately; mixture should not be chewed or warmed. For patients with difficulty swallowing, use of granules may be easiest.
Granules: Empty into container with 1 tablespoon of water and stir; leave 2-3 minutes to thicken. Stir and drink within 30 minutes. If any medicine remains after drinking, add more water, stir and drink immediately.
Tablet (Canadian formulation, not available in U.S.): Swallow whole or may be dispersed in a half a glass of noncarbonated water. Stir until tablets disintegrate, leaving a liquid containing pellets. Drink contents within 30 minutes. Do not chew or crush pellets. After drinking, rinse glass with water and drink.
Administration: I.V.
May be administered by injection (?3 minutes), intermittent infusion (10-30 minutes), or continuous infusion for up to 72 hours (Sung, 2009). Flush line prior to and after administration with NS, LR, or D5W.
Administration: Other
Nasogastric tube:
Capsule: Open capsule and place intact granules into a 60 mL syringe; mix with 50 mL of water. Replace plunger and shake vigorously for 15 seconds. Ensure that no granules remain in syringe tip. Do not administer if pellets dissolve or disintegrate. Use immediately after preparation. After administration, flush nasogastric tube with additional water.
Granules: Delayed release oral suspension granules can also be given by nasogastric or gastric tube. Add 15 mL of water to a syringe, add granules from packet. Shake the syringe, leave 2-3 minutes to thicken. Shake the syringe and administer through nasogastric or gastric tube (French size 6 or greater) within 30 minutes. Refill the syringe with 15 mL of water, shake and flush nasogastric/gastric tube.
Tablet (Canadian formulation, not available in U.S.): Disperse tablets in 50 mL of noncarbonated water. Stir until tablets disintegrate leaving a liquid containing pellets. After administration, flush with additional 25-50 mL of water to clear the syringe and tube.
Administration: I.V. Detail
pH: 9-11
Monitoring Parameters
Susceptibility testing recommended in patients who fail H. pylori eradication regimen (esomeprazole, clarithromycin, and amoxicillin). Monitor for rebleeding in patients with peptic ulcer bleed.
Dietary Considerations
Take at least 1 hour before meals; best if taken before breakfast. The contents of the capsule may be mixed in applesauce or water; pellets also remain intact when exposed to orange juice, apple juice, and yogurt.
Patient Education
Take as directed, 1 hour before eating at same time each day. Swallow capsule whole; do not crush or chew. If you cannot swallow capsule whole, open capsule, mix contents with 1 tablespoon of applesauce, and swallow immediately; do not chew mixture. Do not store for future use. You may experience headache; constipation (increased exercise, fluids, fruit, or fiber may help); diarrhea; or abdominal pain (should diminish with use). Report persistent headache, diarrhea, constipation, abdominal pain, changes in urination or pain on urination, CNS changes, persistent muscular aches or pain, ringing in ears or visual changes, or other adverse reactions. Breast-feeding precaution: Breast-feeding is not recommended.
Geriatric Considerations
Dose adjustment is not necessary.
Additional Information
Esomeprazole is the S-isomer of omeprazole.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information:
Acute ulcer: Postendoscopy therapy: In a multicenter, double-blind trial conducted in 16 countries, 767 patients with peptic ulcer bleeding from a single gastric or duodenal source with high-risk features were randomized to intravenous esomeprazole (80 mg bolus over 30 minutes, followed by a continuous infusion of 8 mg/hour for a total of 72 hours) or placebo. After completion of intravenous therapy, all patients were administered oral esomeprazole 40 mg once daily for an additional 27 days. The use of intravenous esomeprazole demonstrated a significant reduction in the primary end point of clinically significant rebleeding within 72 hours (5.9% vs 10.3%, p=0.026). Although endoscopic therapy was not standardized, the efficacy of esomeprazole was not affected (Sung, 2009).
Intravenous omeprazole has also been studied in prevention of rebleeding in ulcer patients who are at high risk for rebleeding (endoscopic findings of active bleeding or nonbleeding visible vessel) after successful hemostasis (Lau, 2000; Lin, 1998).
Lin and his group treated 100 ulcer patients (actively bleeding ulcers or ulcers with nonbleeding visible vessels) endoscopically and then randomized them to cimetidine (300 mg bolus followed by 50 mg/hour infusion) or omeprazole (40 mg bolus, ~7 mg/hour infusion) for 72 hours. Patients were discharged on the oral form of the drug arm they were assigned to. The omeprazole group maintained an intragastric pH >6 for about 84% of the infusion duration, while the cimetidine group maintained their pH >6 only about 50% of the time. Rebleeding occurred significantly more often in the cimetidine group.
Lau and his colleagues treated patients with actively bleeding ulcers or ulcers with nonbleeding visible vessels with an epinephrine infusion followed by thermocoagulation. They were then randomized to omeprazole (80 mg bolus followed by a continuous infusion of 8 mg/hour for 72 hours) or placebo. All patients were discharged on oral omeprazole (20 mg/day) for 8 weeks and received H. pylori treatment if indicated. The primary goal was to evaluate the rate of rebleeding during the first 30 days after endoscopy. Two hundred and forty patients were enrolled with randomization of 120 into each group. Bleeding recurred in significantly more patients receiving placebo than omeprazole infusion. The authors concluded that after endoscopic therapy, omeprazole reduces the risk of rebleeding in patients with actively bleeding ulcers or ulcers with nonbleeding visible vessels.
Acute ulcer: Pre-endoscopy therapy: Lau and associates (2007) evaluated the effects of preemptive infusion of omeprazole before endoscopy in upper gastrointestinal bleeding. Consecutive patients (638) were stabilized and then randomly assigned to intravenous omeprazole (80 mg bolus followed by a continuous infusion of 8 mg/hour) or placebo infusion before endoscopy the next morning. The primary endpoint was the need for endoscopic therapy (eg, epinephrine, thermocoagulation). Seven patients were excluded from the analysis. The need for endoscopic treatment was significantly lower in the omeprazole group (60/314 patients; 19%) than in the placebo group (90/317; 28%). The active treatment group had a significantly shorter hospital stay. Duration of infusion before endoscopy was similar in both groups (~8-21 hours).
Stress ulcer prophylaxis: The 2008 Surviving Sepsis Campaign guidelines recommend that stress ulcer prophylaxis using an H2 blocker (Grade 1A) or proton pump inhibitor (Grade 1B) be given to patients with severe sepsis to prevent upper GI bleed. Benefit of prevention of upper GI bleed must be weighed against potential effect of increased stomach pH on development of ventilator-associated pneumonia.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation)
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause headache
Mental Health: Effects on Psychiatric Treatment
The clearance of diazepam is decreased by 45% with concomitant use, resulting in increased diazepam levels and potential for toxicity; monitor
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions (especially those dependent on cytochrome P450 metabolism or those dependent on an acid environment for absorption). Monitor response and adverse reactions at beginning of therapy and periodically throughout therapy. Assess knowledge/teach appropriate use of this medication, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian availability
Note: Strength expressed as base
Capsule, delayed release, as magnesium:
Nexium®: 20 mg, 40 mg
Granules, for oral suspension, delayed release, as magnesium:
Nexium®: 10 mg/packet (30s); 20 mg/packet (30s); 40 mg/packet (30s)
Nexium® [CAN]: 10 mg/packet (28s)
Injection, powder for reconstitution, as sodium:
Nexium®: 20 mg, 40 mg [contains edetate sodium]
Tablet, extended release, as magnesium:
Nexium® [CAN]: 20 mg, 40 mg [not available in U.S.]
Pricing: U.S. (www.drugstore.com)
Capsule, delayed release (NexIUM)
20 mg (30): $181.29
40 mg (30): $162.99
References
Andersson T, Hasan-Alin M, Hasselgren G, et al, “Drug Interactions Studies With Esomeprazole, the (S)-Isomer of Omeprazole,” Clin Pharmacokinet, 2001, 40(7):523-37.
Blume H, Donath F, Warnke A, et al, “Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors,” Drug Saf, 2006, 29(9): 769-84.
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International Brand Names
Lexi-Comp.com
Last full review/revision August 2009
Content last modified August 2009
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