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Special Alerts
Proton Pump Inhibitors (Esomeprazole, Omeprazole): Evidence Does Not Suggest Increased Rates of Cardiac Events - Results of FDA Analysis - Updated, February 2008
The U.S. Food and Drug Administration (FDA) and Health Canada reviews of esomeprazole (Nexium®) and omeprazole (Prilosec® [U.S.]/Losec® [CAN]) find no evidence of increased risk of cardiac events related to these medications. In May 2007, AstraZeneca, the manufacturer of Nexium® (esomeprazole) and Prilosec® (U.S.)/Losec® (CAN) (omeprazole), notified both regulatory agencies of concerns regarding a possible association between long-term use of esomeprazole or omeprazole and cardiovascular side effects based on the results of two small, nonblinded, long-term, European clinical trials of patients with GERD. Patients in these trials were randomized to antireflux surgery (fundoplication) or esomeprazole or omeprazole treatment. In these trials, initial data suggested that patients using either of these proton pump inhibitors experienced more heart attacks, heart failure, and cardiac deaths than patients who had surgery. As a result, the FDA and Health Canada issued public notifications regarding these results in August 2007.
The FDA and Health Canada evaluated the two studies, other published trials, and an analysis of postmarketing safety data from the FDA and WHO since that time, and issued independent statements saying that preliminary reviews do not confirm the existence of cardiovascular risk. Upon further analysis of additional information submitted to the FDA and Health Canada by the manufacturer, both regulatory agencies have confirmed their respective preliminary reviews of the evidence, and are recommending that healthcare providers continue to prescribe (and patients continue to use) these products as described within their labeling.
For more information, healthcare professionals may refer to the following FDA and Health Canada websites:
http://www.fda.gov/cder/drug/early_comm/omeprazole_esomepazole_update.htm
http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_34_e.html
Medication Safety Issues
Sound-alike/look-alike issues:
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
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.
• 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.
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: 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, interstitial nephritis, jaundice, larynx edema, leukocytosis, leukopenia, malaise, micturition increased, migraine, muscular weakness, nervousness, osteoporosis, otitis media, pancreatitis, pancytopenia, paresthesia, pharyngolaryngeal pain, pharyngitis, photosensitivity, polymyalgia rheumatica, polyuria, proteinuria, pruritus ani, rhinorrhea, rigors, sleep disorder, somnolence, Stevens-Johnson syndrome, stomatitis, tachycardia, taste disturbances, thrombocytopenia, 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
Antifungal Agents (Azole Derivatives, Systemic): Proton Pump Inhibitors may decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Exceptions: Miconazole. Risk D: Consider therapy modification
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. Risk C: Monitor therapy
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
Dasatinib: Proton Pump Inhibitors may decrease the absorption of Dasatinib. Risk D: Consider therapy modification
Indinavir: Proton Pump Inhibitors may decrease the absorption of Indinavir. Risk C: Monitor therapy
Iron Salts: Proton Pump Inhibitors may decrease the absorption of Iron Salts. Exceptions: Ferric Gluconate; Iron Dextran Complex; Iron Sucrose. Risk C: Monitor therapy
Methotrexate: Proton Pump Inhibitors may decrease the excretion of Methotrexate. Antirheumatic doses of methotrexate probably hold minimal risk. Risk C: Monitor therapy
Saquinavir: Proton Pump Inhibitors may increase the serum concentration of Saquinavir. Risk C: Monitor therapy
Tipranavir: May decrease the serum concentration of Proton Pump Inhibitors. These data are derived from studies with Ritonavir-boosted Tipranavir. 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 15°C to 30°C (59°F to 86°F). Protect from light. 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.
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)
Symptomatic GERD: 20 mg once daily for 4 weeks; may continue an additional 4 weeks if symptoms persist
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
Helicobacter pylori eradication: 40 mg once daily for 10 days; requires combination therapy Note: Various regimens available.
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.: GERD: 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) or infusion (10-30 minutes). 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)
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 (boiled milk, yogurt, or buttermilk may help); 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
Acute ulcer: Postendoscopy therapy: Intravenous omeprazole has 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 (Lin, 1998; Lau, 2000).
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): $169.25
40 mg (30): $154.99
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.
Cockayne SE, Glet RJ, Gawkrodger DJ, et al, “Severe Erythrodermic Reactions to the Proton Pump Inhibitors Omeprazole and Lansoprazole,” Br J Dermatol,1999, 141(1):173-5.
Lau JY, Leung WK, Wu JC, et al, “Omeprazole Before Endoscopy in Patients With Gastrointestinal Bleeding,” N Engl J Med, 2007, 356(16):1631-40.
Lau JY, Sung JJ, Lee KK, et al, “Effect of Intravenous Omeprazole on Recurrent Bleeding After Endoscopic Treatment of Bleeding Peptic Ulcers,” N Engl J Med, 2000, 343(5):310-6.
Lin HJ, Lo WC, Lee FY, et al, “A Prospective Randomized Comparative Trial Showing That Omeprazole Prevents Rebleeding in Patients With Bleeding Peptic Ulcer After Successful Endoscopic Therapy,” Arch Intern Med, 1998, 158(1):54-8.
Li X-Q, Anderson TB, Ahlstrom M, et al, “Comparison of Inhibitory Effects of the Proton Pump-Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on Human Cytochrome P450 Activities,” Drug Metab Disp, 2004, 32(8):821-7.
Natsch S, Vinks MH, Voogt AK, et al, “Anaphylactic Reactions to Proton-Pump Inhibitors,” Ann Pharmacother, 2000, 34(4):474-6.
Wolfe MM and Sachs G, “Acid Suppression: Optimizing Therapy for Gastroduodenal Ulcer Healing, Gastroesophageal Reflux Disease, and Stress-Related Erosive Syndrome,” Gastroenterology, 2000,118(2 Suppl 1):9-31.
Zhao J, Li J, Hamer-Maansson JE, et al, “Pharmacokinetic Properties of Esomeprazole in Children Aged 1 to 11 Years With Symptoms of Gastroesophageal Reflux Disease: A Randomized, Open-Label Study,” Clin Ther, 2006, 28(11): 1868-76.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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