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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:
Prilosec® may be confused with Plendil®, Prevacid®, predniSONE, prilocaine, Prinivil®, Proventil®, Prozac®
International issues:
Norpramin®: Brand name for desipramine in the U.S.
Pronunciation
(oh MEP ra zole)
U.S. Brand Names
Generic Available
Yes: Delayed release capsule
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Short-term (4-8 weeks) treatment of active duodenal ulcer disease or active benign gastric ulcer; treatment of heartburn and other symptoms associated with gastroesophageal reflux disease (GERD); short-term (4-8 weeks) treatment of endoscopically-diagnosed erosive esophagitis; maintenance healing of erosive esophagitis; long-term treatment of pathological hypersecretory conditions; as part of a multidrug regimen for H. pylori eradication to reduce the risk of duodenal ulcer recurrence
OTC labeling: Short-term treatment of frequent, uncomplicated heartburn occurring ?2 days/week
Use: Unlabeled/Investigational
Healing NSAID-induced ulcers; prevention of NSAID-induced ulcers
Pregnancy Risk Factor
C
Pregnancy Considerations
Crosses the placenta; congenital abnormalities have been reported sporadically following omeprazole use during pregnancy. Based on data collected by the Teratogen Information System (TERIS), it was concluded that therapeutic doses used during pregnancy would be unlikely to pose a substantial teratogenic risk (quantity/quality of data: fair). Because the possibility of harm still exists, the manufacturer recommends use during pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus.
Lactation
Enters breast milk/not recommended
Contraindications
Hypersensitivity to omeprazole, substituted benzimidazoles (ie, esomeprazole, lansoprazole, 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).
• Carcinoma: In long-term (2-year) studies in rats, omeprazole produced a dose-related increase in gastric carcinoid tumors. While available endoscopic evaluations and histologic examinations of biopsy specimens from human stomachs have not detected a risk from short-term exposure to omeprazole, further human data on the effect of sustained hypochlorhydria and hypergastrinemia are needed to rule out the possibility of an increased risk for the development of tumors in humans receiving long-term therapy.
Disease-related concerns:
• Gastric malignancy: Relief of symptoms does not preclude the presence of a gastric malignancy.
• Hepatic impairment: Bioavailability may be increased in patients with hepatic dysfunction.
Special populations:
• Asian ethnicity: Bioavailability may be increased in patients of Asian descent.
• Elderly: Bioavailability may be increased in the elderly.
• Pediatrics: Safety and efficacy have not been established in children <2 years of age. OTC and oral suspension are not approved for use in children <18 years of age.
Other warnings/precautions:
• Self-medication (OTC use): When used for self-medication (OTC), do not use for >14 days; treatment should not be repeated more often than every 4 months.
Adverse Reactions
1% to 10%:
Central nervous system: Headache (3% to 7%), dizziness (2%)
Dermatologic: Rash (2%)
Gastrointestinal: Diarrhea (3% to 4%), abdominal pain (2% to 5%), nausea (2% to 4%), vomiting (2% to 3%), flatulence (?3%), acid regurgitation (2%), constipation (1% to 2%), taste perversion
Neuromuscular & skeletal: Weakness (1%), back pain (1%)
Respiratory: Upper respiratory infection (2%), cough (1%)
1%, postmarketing, and/or case reports (adverse event occurrence may vary based on formulation): Abdominal swelling, abnormal dreams, aggression, agitation, agranulocytosis, alkaline phosphatase increased, allergic reactions, alopecia, ALT/AST increased, anaphylaxis, anemia, angina, angioedema, anorexia, anxiety, apathy, atrophic gastritis, benign gastric polyps, bilirubin increased, blurred vision, bradycardia, chest pain, cholestatic hepatitis, confusion, creatinine increased, depression, diaphoresis, double vision, dry skin, epistaxis, erythema multiforme, esophageal candidiasis, fatigue, fecal discoloration, fever, gastroduodenal carcinoids, GGT increased, glycosuria, gynecomastia, hallucinations, hematuria, hemifacial dysesthesia, hemolytic anemia, hepatic encephalopathy, hepatic failure, hepatic necrosis, hepatitis, hepatocellular hepatitis, hyperhidrosis, hypertension, hypoglycemia, hyponatremia, insomnia, interstitial nephritis, irritable colon, jaundice, joint pain, leg pain, leukocytosis, leukopenia, liver disease (hepatocellular, cholestatic, mixed), malaise, microscopic pyuria, mucosal atrophy (tongue), muscle cramps, muscle weakness, myalgia, nervousness, neutropenia, ocular irritation, optic atrophy, optic neuritis, optic neuropathy (anterior ischemic), pain, palpitation, pancreatitis, pancytopenia, paresthesia, peripheral edema, petechiae, pharyngeal pain, photosensitivity, pneumothorax, proteinuria, pruritus, psychic disturbance, purpura, rash, skin inflammation, somnolence, Stevens-Johnson syndrome, stomatitis, tachycardia, taste perversion, testicular pain, thrombocytopenia, tinnitus, toxic epidermal necrolysis, tremor, urinary frequency, urinary tract infection, urticaria, vertigo, weight gain, xerophthalmia, xerostomia
Metabolism/Transport Effects
Substrate of CYP2A6 (minor), 2C9 (minor), 2C19 (major), 2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2C9 (moderate), 2C19 (strong), 2D6 (weak), 3A4 (weak); Induces CYP1A2 (weak)
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
Cilostazol: Omeprazole may enhance the adverse/toxic effect of Cilostazol. Risk D: Consider therapy modification
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
Clozapine: Omeprazole may decrease the serum concentration of Clozapine. Omeprazole may increase the serum concentration of Clozapine. Risk C: Monitor therapy
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP2C9 Substrates (High risk with Highly Effective Inhibitors): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). 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
Nelfinavir: Omeprazole may decrease the serum concentration of Nelfinavir. Risk C: Monitor therapy
Phenytoin: Proton Pump Inhibitors may increase the serum concentration of Phenytoin. 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
Warfarin: Proton Pump Inhibitors may increase the serum concentration of Warfarin. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may cause gastric mucosal irritation).
Food: Food delays absorption.
Storage
Store at 15°C to 30°C (59°F to 86°F). Protect from light.
Mechanism of Action
Proton pump inhibitor; suppresses gastric basal and stimulated acid secretion by inhibiting the parietal cell H+/K+ ATP pump
Pharmacodynamics/Kinetics
Onset of action: Antisecretory: ?1 hour
Peak effect: 0.5-3.5 hours
Duration: Up to 72 hours
Protein binding: ?95%
Metabolism: Extensively hepatic to inactive metabolites
Bioavailability: Oral: ?30% to 40%; increased in Asian patients and patients with hepatic dysfunction
Half-life elimination: Delayed release capsule: 0.5-1 hour
Excretion: Urine (77% as metabolites, very small amount as unchanged drug); feces
Dosage
Oral:
Children ?2 years: GERD or other acid-related disorders:
<20 kg: 10 mg once daily
?20 kg: 20 mg once daily
Adults:
Active duodenal ulcer: 20 mg/day for 4-8 weeks
Gastric ulcers: 40 mg/day for 4-8 weeks
Symptomatic GERD: 20 mg/day for up to 4 weeks
Erosive esophagitis: 20 mg/day for 4-8 weeks; maintenance of healing: 20 mg/day for up to 12 months total therapy (including treatment period of 4-8 weeks)
Helicobacter pylori eradication: Dose varies with regimen: 20 mg once daily or 40 mg/day as single dose or in 2 divided doses; requires combination therapy with antibiotics
Pathological hypersecretory conditions: Initial: 60 mg once daily; doses up to 120 mg 3 times/day have been administered; administer daily doses >80 mg in divided doses
Frequent heartburn (OTC labeling): 20 mg/day for 14 days; treatment may be repeated after 4 months if needed
Dosage adjustment in hepatic impairment: Specific guidelines are not available; bioavailability is increased with chronic liver disease
Administration: Oral
Capsule: Should be swallowed whole; do not chew or crush. Best if taken before breakfast. Delayed release capsule may be opened and contents added to applesauce. Administration via NG tube should be in an acidic juice.
Tablet: Should be swallowed whole; do not crush or chew.
Dietary Considerations
Should be taken on an empty stomach; best if taken before breakfast.
Patient Education
Take as directed, before eating. Do not crush or chew capsules. Delayed release capsule may be opened and contents added to applesauce. Avoid alcohol. You may experience anorexia; small frequent meals may help to maintain adequate nutrition. Report severe headache or unresolved severe diarrhea. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
Geriatric Considerations
In clinical trials, the incidence of side effects in the elderly is no different than that of younger adults (?65 years) despite slight decrease in elimination and increase in bioavailability. Bioavailability may be increased in the elderly (?65 years of age), however, dosage adjustments are not necessary.
Anesthesia and Critical Care Concerns/Other Considerations
A 2 mg/mL oral omeprazole solution (Simplified Omeprazole Solution) can be prepared with five omeprazole 20 mg delayed release capsules and 50 mL 8.4% sodium bicarbonate. Empty capsules into beaker. Add sodium bicarbonate solution. Gently stir (about 15 minutes) until a white suspension is formed. Transfer to amber-colored syringe or bottle. Stable for 14 days at room temperature or for 30 days under refrigeration.
DiGiancinto JL, Olsen KM, Bergman KL, et al, “Stability of Suspension Formulations of Lansoprazole and Omeprazole Stored in Amber-Colored Plastic Oral Syringes,” Ann Pharmacother, 2000, 34:600-5.
Quercia R, Fan C, Liu X, et al, “Stability of Omeprazole in an Extemporaneously Prepared Oral Liquid,” Am J Health Syst Pharm, 1997, 54:1833-6.
Sharma V, “Comparison of 24-Hour Intragastric pH Using Four Liquid Formulations of Lansoprazole and Omeprazole,” Am J Health Syst Pharm, 1999, 56(Suppl 4):S18-21.
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: Taste perversion, dry mouth, esophageal candidiasis, and mucosal atrophy (tongue).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness, agitation, aggression, depression, confusion, insomnia, nervousness, anxiety, or hallucinations; may rarely cause sedation
Mental Health: Effects on Psychiatric Treatment
May inhibit the metabolism of diazepam; monitor for increased sedation
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 a acid environment for absorption). Monitor therapeutic effectiveness 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.
Capsule, delayed release: 10 mg, 20 mg
Prilosec®: 10 mg, 20 mg, 40 mg
Tablet, delayed release:
Prilosec OTC™: 20 mg
Pricing: U.S. (www.drugstore.com)
Capsule, delayed release (Omeprazole)
10 mg (30): $32.99
20 mg (90): $63.97
Capsule, delayed release (Prilosec)
20 mg (30): $148.70
40 mg (30): $224.95
Tablet, EC (Prilosec OTC)
20 mg (14): $19.99
Extemporaneously Prepared
A 2 mg/mL oral omeprazole solution (Simplified Omeprazole Solution) can be prepared with five omeprazole 20 mg delayed release capsules and 50 mL 8.4% sodium bicarbonate. Empty capsules into beaker. Add sodium bicarbonate solution. Gently stir (about 15 minutes) until a white suspension is formed. Transfer to amber-colored syringe or bottle. Stable for 14 days at room temperature or for 30 days under refrigeration.
DiGiancinto JL, Olsen KM, Bergman KL, et al, “Stability of Suspension Formulations of Lansoprazole and Omeprazole Stored in Amber-Colored Plastic Oral Syringes,” Ann Pharmacother, 2000, 34:600-5.
Quercia R, Fan C, Liu X, et al, “Stability of Omeprazole in an Extemporaneously Prepared Oral Liquid,” Am J Health Syst Pharm, 1997, 54:1833-6.
Sharma V, “Comparison of 24-hour Intragastric pH Using Four Liquid Formulations of Lansoprazole and Omeprazole,” Am J Health Syst Pharm, 1999, 56(Suppl 4):S18-21.
Extemporaneous preparation for NG administration (Prilosec®): The manufacturer recommends the use of an acidic juice for preparation to administer via nasogastric (NG) tube. Alternative methods have been described as follows. NG tube administration for the prevention of stress-related mucosal damage in ventilated, critically-ill patients. The manufacturer makes no judgment regarding the safety or efficacy of these practices.
The contents of one or two 20 mg omeprazole delayed release capsules were poured into a syringe; 10-20 mL of an 8.4% sodium bicarbonate solution was withdrawn in the syringe; 30 minutes were allowed for the enteric-coated omeprazole granules to break down. The resulting milky substance was shaken prior to administration. The NG tube was then flushed with 5-10 mL of water and then clamped for at least 1 hour. Patients received omeprazole 40 mg once, then 40 mg 6-8 hours later, then 20 mg once daily using this technique.
Another study used a different technique. The omeprazole delayed release capsule (20 mg or 40 mg) was opened; then the intact granules were poured into a container holding 30 mL of water. With the plunger removed, 1/3 to 1/2 of the granules were then poured into a 30 mL syringe which was attached to a nasogastric tube (NG). The plunger was replaced with 1 cm of air between the granules and the plunger top while the plunger was depressed. This process was repeated until all the granules were flushed, then a final 15 mL of water was flushed through the tube. Patients who received omeprazole 40 mg in this manner had a more predictable increase in intragastric pH than patients who received omeprazole 20 mg.
References
Andersson T, “Omeprazole Drug Interaction Studies,” Clin Pharmacokinet, 1991, 21(3):195-212.
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.
Balian JD, Sukhova N, Harris JW, et al, “The Hydroxylation of Omeprazole Correlates With S-Mephenytoin Metabolism: A Population Study,” Clin Pharmacol Ther, 1995, 57(6):662-9.
Berardi RR and Dunn-Kucharski VA, “Omeprazole: Defining Its Role in Gastroesophageal Reflux Disease,” Hosp Formul, 1995, 30:216-25.
Beutler M, Hartmann K, Kuhn M, et al, “Arthralgias on Omeprazole,” BMJ, 1994, 309(6969):1620.
Blume H, Donath F, Warnke A, et al, “Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors,” Drug Saf, 2006, 29(9): 769-84.
Broussard CN and Richter JE, “Treating Gastro-oesophageal Reflux Disease During Pregnancy and Lactation: What Are the Safest Therapy Options?” Drug Saf, 1998, 19(4):325-37.
Carvajal A and Martin Arias LH, “Gynecomastia and Sexual Disorders After the Administration of Omeprazole,” Am J Gastroenterol, 1995, 90(6):1028-9.
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.
Dellinger RP, Levy MM, Carlet JM, et al, “Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008,” Intensive Care Med, 2008, 34(1): 17-60. Available at http://www.survivingsepsis.org/system/files/images/2008_20International_20SSC_20Guidelines_1_.pdf
Epelde Gonzalo FD, Boada Montagut L, and Tomas Vecina S, “Exfoliative Dermatitis Related to Omeprazole,” Ann Pharmacother, 1995, 29(1):82-3.
Gunasekaran TS and Hassall EG, “Efficacy and Safety of Omeprazole for Severe Gastroesophageal Reflux in Children,” J Pediatr, 1993, 123(1):148-54.
Kane DL, “Administration of Omeprazole (Prilosec®) in the Atypical Patient,” Int J Pharm Compounding, 1997, 1(1):13.
Kato S, Ebina K, Fujii K, et al, “Effect of Omeprazole in the Treatment of Refractory Acid-Related Diseases in Childhood: Endoscopic Healing and Twenty-Four Hour Intragastric Acidity,” J Pediatr, 1996, 128(3):415-21.
Kraus A and Flores-Suarez LF, “Acute Gout Associated With Omeprazole,” Lancet, 1995, 345(8947):461-2.
Larner AJ and Lendrum R, “Oesophageal Candidiasis After Omeprazole Therapy,” Gut, 1992, 33(6):860-1.
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.
Lindquist M and Edwards IR, “Endocrine Adverse Effects of Omeprazole,” Br Med J, 1992, 305(6851):451-2.
Natsch S, Vinks MH, Voogt AK, et al, “Anaphylactic Reactions to Proton-Pump Inhibitors,” Ann Pharmacother, 2000, 34(4):474-6.
Ottervanger JP, Stricker BH, Kappelle JW, et al, “Omeprazole-Associated Agranulocytosis,” Eur J Haematol, 1995, 54(4):279-80.
Soll AH, Weinstein WM, Kurata J, et al, “Nonsteroidal Anti-inflammatory Drugs and Peptic Ulcer Disease,” Ann Intern Med, 1991, 114(4):307-19.
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.
Woods DJ and McClintock AD, “Omeprazole Administration,” Ann Pharmacother, 1993, 27(5):651.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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