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DR.REDDY'S LAB
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omeprazole dr 20 mg capsule (generic prilosec)

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Uses

Omeprazole is used in adults for the short-term treatment of active duodenal and benign gastric ulcer. Omeprazole also is used in combination with clarithromycin (dual therapy) or with amoxicillin and clarithromycin (triple therapy) for the treatment of Helicobacter pylori infection and duodenal ulcer disease in adults. Omeprazole also has been used in other multiple-drug regimens (with or without clarithromycin) for the treatment of H. pylori infection associated with peptic ulcer disease. Omeprazole is used in adults and children 1 year of age and older for short-term treatment and symptomatic relief of gastroesophageal reflux disease (e.g., erosive esophagitis, heartburn) and as maintenance therapy following healing of erosive esophagitis to reduce its recurrence. The drug also is used as self-medication for short-term treatment and symptomatic relief of frequent heartburn in adults. Omeprazole is used for the long-term treatment of pathologic GI hypersecretory conditions in adults. Omeprazole also is used to decrease the risk of upper GI bleeding in critically ill adults.

Duodenal Ulcer

Acute Therapy

Omeprazole immediate- and delayed-release capsules, omeprazole immediate-release oral suspension, and omeprazole magnesium delayed-release oral suspension are used in adults for the short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer. Antacids may be used concomitantly as needed for pain relief. In controlled studies in patients with endoscopically confirmed duodenal ulcers, reported rates of ulcer healing for omeprazole were substantially higher than those for placebo. In a multicenter, double-blind study in patients with endoscopically confirmed duodenal ulcer, reported rates of ulcer healing for an oral omeprazole dosage of 20 mg each morning or placebo were 41 or 13%, respectively, at 2 weeks and 75 or 27%, respectively, at 4 weeks. Omeprazole also produced greater reductions in daytime and nocturnal pain and antacid consumption than did placebo, with complete relief of pain in most patients usually occurring within 4 weeks after initiation of omeprazole therapy.

Omeprazole appears to be at least as effective as histamine H2-receptor antagonists for short-term treatment of active duodenal ulcer. In a multicenter, controlled study in patients with endoscopically confirmed duodenal ulcers, 42 or 34% of ulcers were healed following oral administration of omeprazole 20 mg each morning or ranitidine 150 mg twice daily, respectively, for 2 weeks and 82 or 63%, respectively, were healed after 4 weeks of therapy. In another multicenter, controlled study in patients with endoscopically confirmed duodenal ulcers, ulcer healing occurred faster in patients given omeprazole 20 or 40 mg daily compared with patients given ranitidine 150 mg twice daily. Ulcer healing rates averaged 83 or 53% at 2 weeks, 97-100 or 82% at 4 weeks, and 100 or 94% at 8 weeks with the omeprazole regimens or ranitidine 150 mg twice daily, respectively. In several studies, ulcer healing was less likely in patients who were smokers and in those with large ulcers than in other patients.

Most patients with duodenal ulcer respond to omeprazole therapy during the initial 4-week course of therapy; an additional 4 weeks of therapy may contribute to healing in some patients.

Omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension are used in combination with clarithromycin and amoxicillin (triple therapy) for the treatment of H. pylori infection and duodenal ulcer disease in adults. Omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension also are used in combination with clarithromycin (dual therapy) in adults for the treatment of H. pylori infection and duodenal ulcer disease. Omeprazole also has been used in other multiple-drug regimens for the treatment of H. pylori infection associated with peptic ulcer disease. Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers; long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. For additional information on the association of this infection with these and other GI conditions, . Conventional antiulcer therapy with histamine H2-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori, and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year). The American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection. Although 3-drug regimens consisting of a bismuth salt (e.g., bismuth subsalicylate) and 2 anti-infective agents (e.g., tetracycline or amoxicillin plus metronidazole) administered for 10-14 days have been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori-associated peptic ulcer disease, current evidence principally from studies in Europe suggests that 1 week of such therapy provides comparable H. pylori eradication rates. Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, histamine H2-receptor antagonist) also have been used successfully for H. pylori eradication, and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.

Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti-H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance. Therefore, the ACG and many clinicians currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.

Therapy with an antisecretory drug and a single anti-infective agent (i.e., ''dual therapy'') also has been used successfully for treatment of H. pylori infection. However, while some studies demonstrate that certain 2-drug anti-H. pylori regimens (e.g., clarithromycin-omeprazole, ranitidine bismuth citrate-omeprazole, amoxicillin-omeprazole) can successfully eradicate H. pylori infection and prevent recurrence of duodenal ulcer at least in the short term (e.g., at 6 months following completion of anti-H. pylori therapy), the ACG and some clinicians currently state that anti-H. pylori regimens consisting of at least 3 drugs (e.g., 2 anti-infective agents plus a proton-pump inhibitor) are recommended because of enhanced H. pylori eradication rates, decreased failures due to resistance, and shorter treatment periods compared with those apparently required with 2-drug regimens. Additional randomized, controlled studies comparing various anti-H. pylori regimens are needed to clarify optimum drug combinations, dosages, and durations of treatment for H. pylori infection. For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, .

Gastric Ulcer

Acute Therapy

Omeprazole immediate- and delayed-release capsules, omeprazole immediate-release oral suspension, and omeprazole magnesium delayed-release oral suspension are used in adults for the short-term treatment and symptomatic relief of active benign gastric ulcer. In controlled studies in patients with endoscopically confirmed gastric ulcers, reported rates of ulcer healing with omeprazole therapy were substantially higher than those with placebo. In a multicenter, double-blind study in patients with endoscopically confirmed gastric ulcer, reported rates of ulcer healing with omeprazole 20 or 40 mg daily or placebo were 48, 56, or 31%, respectively, at 4 weeks and 75, 83, or 48%, respectively, at 8 weeks. In patients with an ulcer larger than 1 cm in size, the percentage of patients with healed ulcers at 8 weeks was greater with the 40-mg dosage than with the 20-mg dosage of omeprazole. Otherwise, for patients with smaller ulcers, no difference in ulcer healing rates between the 40- and 20-mg dosages was observed.

In a multicenter, comparative study in patients with endoscopically confirmed gastric ulcer, ulcer healing occurred at 4 weeks in 64 or 78% of patients receiving omeprazole 20 or 40 mg daily, respectively, compared with 56% of those receiving ranitidine 150 mg twice daily; at 8 weeks, 82, 91, or 78% of patients receiving omeprazole 20 mg daily, omeprazole 40 mg daily, or ranitidine 150 mg twice daily, respectively, had healed ulcers.

Crohn's Disease-associated Ulcers

Although evidence currently is limited, proton-pump inhibitors have been used for gastric acid-suppressive therapy as an adjunct in the symptomatic treatment of upper GI Crohn's disease, including esophageal, gastroduodenal, and jejunoileal disease. The drugs have been used for symptomatic relief of upper GI symptoms and to promote healing of Crohn's disease-associated peptic ulcer disease. Most evidence of efficacy to date has been from case studies in patients with Crohn's-associated peptic ulcer disease unresponsive to other therapies (e.g., histamine H2-receptor antagonists, cytoprotective agents, antacids, and/or sucralfate). Omeprazole (20 or 40 mg daily) was associated with resolution of symptoms and ulcer healing within about 2 and 4 weeks, respectively, in some patients, while others required several months of acid-suppressive therapy. Subsequent symptomatic relief may be maintained with prolonged acid-suppressive therapy with a proton-pump inhibitor or H2-receptor antagonist, with or without an immunosuppressive agent (e.g., azathioprine). Adjunctive inhibition of gastric acid secretion is likely to be more effective in promoting ulcer healing in Crohn's disease than corticosteroid therapy. Pending accumulation of more definitive evidence, some experts and clinicians state that therapy with a proton-pump inhibitor may be a useful adjunct to provide symptomatic relief and promote ulcer healing in patients with upper GI Crohn's disease.

For further information on the management of Crohn's Disease,

Gastroesophageal Reflux

Omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension are used in adults and children 1 year of age and older, and omeprazole immediate-release capsules and immediate-release oral suspension are used in adults for the short-term treatment and symptomatic relief of gastroesophageal reflux disease (GERD) (e.g., erosive esophagitis, heartburn) and as maintenance therapy following healing of erosive esophagitis to prevent its recurrence. Safety and efficacy of omeprazole immediate-release capsules and immediate-release oral suspension have not been established in pediatric patients. Omeprazole magnesium delayed-release capsules are used in adults as self-medication for the short-term treatment and symptomatic relief of frequent heartburn.

GERD is considered to be a chronic disease, and many patients with GERD require long-term, even lifelong, treatment. Typical GERD symptoms include heartburn and/or regurgitation, often occurring after meals, especially large and/or fatty meals. The symptoms often are aggravated by recumbency or bending, and are relieved by antacids. GERD symptoms generally are controlled by appropriate medical therapy. Suppression of gastric acid secretion is considered by the ACG to be the mainstay of treatment for GERD, and a proton-pump inhibitor or histamine H2-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease. The ACG states that proton-pump inhibitors are more effective than histamine H2-receptor antagonists for acute therapy of GERD and also are appropriate as maintenance therapy in many patients with the disease. Lifestyle modifications (e.g., elevation of the head of the bed, decreased dietary fat intake, smoking cessation, avoidance of recumbency for 3 hours after a meal, avoidance of foods that increase reflux, weight loss) should be initiated and continued throughout the course of treatment.

Acute Therapy

Omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension are used in adults and children 1 year of age and older, and omeprazole immediate-release capsules and immediate-release oral suspension are used in adults for the short-term (4-8 weeks) treatment of endoscopically diagnosed erosive esophagitis in patients with GERD. Omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension are used in adults and children 1 year of age and older, and omeprazole immediate-release capsules and immediate-release oral suspension are used in adults for the short-term (4-8 weeks) treatment of symptomatic GERD (e.g., heartburn). Potential benefits of omeprazole in gastroesophageal reflux and esophagitis are thought to result principally from reduced acidity of gastric contents induced by the drug and resultant reduced irritation of esophageal mucosa; the drug can effectively relieve symptoms of esophagitis (e.g., heartburn) and promote healing of ulcerative and erosive lesions.

Drug Selection Considerations

The ACG states that proton-pump inhibitors are more effective (i.e., provide more frequent and more rapid symptomatic relief and healing of esophagitis) than histamine H2-receptor antagonists in the treatment of GERD. Although higher doses and more frequent administration of histamine H2-receptor antagonists appear to increase their efficacy, such dosages are less effective than proton-pump inhibitor therapy. In addition, the ACG states that proton-pump inhibitors provide greater control of acid reflux than do prokinetic agents (e.g., cisapride [no longer commercially available in the US], metoclopramide) without the risk of severe adverse effects associated with these agents. Correction of esophageal and gastric motility defects that cause GERD might theoretically control the disease and make suppression of normal gastric acid secretion unnecessary, and prokinetic agents have been used in the treatment of GERD. However, cisapride was withdrawn from the US market because of its association with serious cardiac arrhythmias and death , and metoclopramide frequently is associated with adverse CNS effects (e.g., restlessness, drowsiness, fatigue, lassitude). The ACG states that the frequent occurrence of adverse CNS effects has appropriately decreased regular use of metoclopramide for treatment of GERD. Cisapride or metoclopramide therapy appears to provide symptomatic relief and esophageal healing as effectively as a standard dosage of a histamine H2-receptor antagonist, and improved efficacy has been reported when a prokinetic agent has been used in combination with a histamine H2-receptor antagonist. Bethanechol, a cholinergic drug that increases GI motility, may increase lower esophageal sphincter pressure to a small degree, but the ACG states that the drug has limited efficacy in the treatment of GERD.

The ACG states that a histamine H2-receptor antagonist administered daily in divided doses is effective in many patients with less severe GERD, and over-the-counter (OTC) antacids and histamine H2-receptor antagonists are appropriate for self-medication as initial therapy in such individuals. A histamine H2-receptor antagonist is particularly useful when taken before certain activities (e.g., heavy meal, exercise) that may result in acid reflux symptoms in some patients.

Other Considerations

The ACG states that initial empiric therapy including suppression of gastric acid secretion and lifestyle modification is appropriate for patients with typical symptoms of uncomplicated GERD, and a diagnosis of GERD is reasonably assumed in those who respond to such therapy. Diagnostic testing (e.g., endoscopy, endoscopic biopsy, ambulatory pH testing, esophageal manometry) may be indicated when empiric drug therapy is unsuccessful, continuous medical therapy is required for symptomatic relief, chronic symptoms occur in patients at risk for esophageal metaplasia (e.g., Barrett's epithelium), or manifestations suggestive of complicated disease (e.g., dysphagia, bleeding, weight loss, choking [acid causing cough, shortness of breath, or hoarseness], chest pain) occur. In patients with symptoms refractory to empiric drug therapy, the diagnosis of GERD should be carefully confirmed with diagnostic testing before chronic, high-dose acid-suppression therapy or antireflux surgery is undertaken. Higher dosage and a longer therapeutic trial of a gastric antisecretory agent may be required in patients with atypical or extraesophageal symptoms (e.g., chronic chest pain, cough, hoarseness, asthma, dental erosions).

Clinical Trials

In a controlled study in patients with manifestations of GERD (e.g., heartburn) and the absence of erosive esophageal lesions, symptomatic improvement with omeprazole was better than that with placebo. Complete resolution of heartburn was reported in 56, 36, or 14% of patients with endoscopically confirmed GERD and in 46, 31, or 13% of all enrolled patients after up to 4 weeks of therapy with omeprazole 20 mg daily, omeprazole 10 mg daily, or placebo, respectively.

In an uncontrolled, open-label study of 113 pediatric patients 2-16 years of age with a history of symptoms suggestive of nonerosive GERD, patients received an omeprazole dosage of 10 or 20 mg once daily (based on body weight) either as an intact capsule or as an open capsule in applesauce. The number and intensity of either pain-related symptoms or vomiting/regurgitation episodes was successfully reduced in 60 or 59% of those receiving omeprazole 10 or 20 mg, respectively. In another uncontrolled study in 12 children 1-2 years of age with a history of clinically diagnosed GERD, administration of omeprazole (0.5-1.5 mg/kg as an opened capsule in 8.4% sodium bicarbonate solution) for 8 weeks reduced episodes of vomiting/regurgitation from baseline by at least 50% in 9 patients (75%).

In controlled studies in patients with endoscopically diagnosed erosive esophagitis and symptoms of GERD, reported rates of healing with omeprazole were higher than those with placebo or an H2-receptor antagonist. Healing rates from a controlled study were 39, 45, or 7% at 4 weeks and 74, 75, or 14% at 8 weeks for omeprazole 20 mg daily, 40 mg daily, or placebo, respectively. In controlled studies in patients with esophagitis, reported rates of healing were 57-74 or 27-43% at 4 weeks and 78-87 or 28-56% at 8 weeks in patients given omeprazole or ranitidine, respectively. Patients receiving omeprazole reported faster relief of daytime and nocturnal heartburn than those receiving placebo or an H2-receptor antagonist. Omeprazole also has been shown to be effective in promoting healing and providing symptomatic relief in a substantial proportion of patients who failed to respond to an adequate course of relatively high dosages of an H2-receptor antagonist.

In an uncontrolled, open-label dose-titration study in 57 pediatric patients aged 1-16 years of age with erosive esophagitis, omeprazole dosages of 0.7-3.5 mg/kg daily were required to promote healing. Dosages were initiated at 0.7 mg/kg daily and if therapeutic goals (intraesophageal pH below 4 for less than 6% of a 24-hour period) were not achieved after 5-14 days of treatment, the dosage was increased to 1.4 mg/kg daily. Based on additional measurements of intraesophageal pH and/or presence of pathologic acid reflux, the dosages were increased up to a maximum dosage of 3.5 mg/kg or 80 mg daily. After titration of omeprazole dosage, patients remained on treatment for 3 months (healing phase); patients with persistent erosive esophagitis after 3 months received a discretionary dosage increase and treatment for an additional 3 months. Erosive esophagitis was healed in 90% of children completing the first course of treatment in the healing phase of the study; 5% received a second treatment course. Healing occurred in 44% of the patients receiving omeprazole 0.7 mg/kg daily, and an additional 28% were healed with 1.4 mg/kg daily. After 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation or vomiting.

Most patients with GERD respond to omeprazole therapy during an initial 8-week course of therapy; however, an additional 4 weeks of therapy may contribute to healing and symptomatic improvement in some patients. Short-term omeprazole therapy for the treatment of GERD will not prevent recurrence following discontinuance of the drug. If symptomatic GERD or erosive esophagitis recur, the manufacturers state that additional 4- to 8-week courses of omeprazole may be given. However, the ACG states that chronic therapy with a proton-pump inhibitor is appropriate in many patients with GERD.

Maintenance Therapy

Omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension are used in adults and children 1 year of age and older, and omeprazole immediate-release capsules and immediate-release oral suspension are used in adults as maintenance therapy following healing of erosive esophagitis to reduce recurrence of the disease. In a multicenter, double-blind study, endoscopically documented remission of esophagitis was maintained at 6 months in 70, 34, or 11% of patients receiving omeprazole 20 mg daily, 20 mg on 3 consecutive days each week, or placebo, respectively. In another multicenter, double-blind study in patients with endoscopically confirmed healed esophagitis, endoscopic remission of esophagitis was maintained at 12 months in 77, 58, or 46% of patients receiving omeprazole 20 mg daily, 10 mg daily, or ranitidine 150 mg twice daily, respectively. However, patients with initial grade 3 or 4 erosive esophagitis required 20 mg of omeprazole daily for maintenance of healing.

In an uncontrolled, open-label study in 46 pediatric patients, maintenance dosages were half the dosages that were required for promotion of healing in 54% of the children studied. The remaining patients required a dosage increase (0.7 to a maximum of 2.8 mg/kg daily) for all or part of the maintenance period. There was no relapse of erosive esophagitis in 41% of the patients, and no symptoms occurred in 63% of the pediatric patients receiving omeprazole maintenance therapy.

Because GERD is a chronic condition, the ACG states that continuous therapy to control symptoms and prevent complications of the disease is appropriate, and chronic, even lifelong, use of a proton-pump inhibitor is effective and appropriate as maintenance therapy in many patients with GERD. Although neither medical nor surgical therapy of GERD appears to result in regression of Barrett's epithelium in the esophagus, chronic use of a proton-pump inhibitor at full dosage decreases the recurrence of esophageal strictures, increases the interval between symptomatic relapses, and may improve esophageal motility. In a double-blind, controlled study, antisecretory therapy had no clinically important effect on Barrett's mucosa in 106 patients receiving omeprazole (40 mg twice daily for 12 months, followed by 20 mg twice daily for 12 months) or ranitidine (300 mg twice daily for 24 months). Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett's mucosa was not achieved.

The frequent marked improvement in symptoms associated with full dosage of a proton-pump inhibitor generally is followed by rapid recurrence of symptoms once the drug is discontinued, and reduced-dosage regimens (e.g., every other day, ''weekend'' dosage) have not been shown to be consistently effective for maintenance therapy. In addition, many patients initially responding to proton-pump inhibitors experience symptomatic relapse and failure of esophageal healing when switched subsequently to a histamine H2-receptor antagonist or prokinetic agent (e.g., cisapride, metoclopramide). Furthermore, prokinetic agents have been associated with severe adverse effects. Cisapride has been withdrawn from the US market because of its association with serious cardiac arrhythmias and death , and metoclopramide frequently is associated with CNS adverse effects (e.g., restlessness, drowsiness, fatigue, lassitude) and may cause irreversible tardive dyskinesia with prolonged use. Once-daily administration of a histamine H2-receptor antagonist at full dosage is not considered to be appropriate therapy for GERD. Although antacids and lifestyle modifications may provide long-term symptomatic control in up to 20% of patients with GERD, frequent symptomatic relapses may occur despite appropriate therapy in up to 50% of patients with chronic gastroesophageal reflux.

Self-Medication

Omeprazole magnesium delayed-release capsules are used in adults 18 years of age or older as self-medication for short-term (14 days) treatment and symptomatic relief of frequent (e.g., 2 or more days a week) heartburn. Because 1-4 days may be required for complete relief of symptoms, omeprazole for self-medication is not intended for the immediate relief of heartburn, and other agents (e.g., antacids, histamine H2-receptor antagonists) may be needed for initial relief. However, some individuals may experience complete relief of symptoms within 24 hours of taking the first dose of omeprazole. In 2 controlled studies, 50% of patients receiving omeprazole 20 mg daily experienced no heartburn during the first day of therapy, and the percentage of patients experiencing complete relief continued to increase in subsequent days; 30% of those receiving placebo experienced no heartburn during the first day of therapy. Omeprazole should not be used for self-medication of occasional heartburn (i.e., heartburn that occurs once weekly or less frequently) or for prevention of occasional meal- or beverage-induced heartburn.

Pathologic GI Hypersecretory Conditions

Omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension are used in adults for the long-term treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas, systemic mastocytosis). The drug reduces gastric acid secretion and associated symptoms (including diarrhea, anorexia, and pain) in patients with these conditions. In dosages ranging from 20 mg every other day to 360 mg daily, omeprazole can maintain basal acid secretion below 5 or 10 mEq/hour in patients who have or have not undergone gastric surgery, respectively. In addition, dosages ranging from 20-360 mg daily have been effective in resolving acid-related pathology in most patients with Zollinger-Ellison syndrome, including those whose symptoms were unresponsive to H2-receptor antagonist therapy.

Upper GI Bleeding

Omeprazole immediate-release oral suspension is used to decrease the risk of upper GI bleeding in critically ill adults. Efficacy of omeprazole was evaluated in a controlled, double-blind randomized clinical trial in critically ill patients who were randomized to receive either omeprazole immediate-release oral suspension (2 doses of 40 mg 6-8 hours apart on the first day, then 40 mg daily) via a gastric tube or IV cimetidine (300 mg loading dose, then 50-100 mg/hour continuously) for up to 14 days. The primary efficacy end point of the study was clinically important upper GI bleeding (defined as bright red blood that did not clear after tube adjustment and 5-10 minutes of lavage or positive test for occult blood in gastric aspirate [''coffee ground material''] for 8 consecutive hours on days 1 and 2, or for 2-4 hours on days 3-14 that did not clear with 100 mL of lavage). Omeprazole was at least as effective as IV cimetidine in preventing clinically important upper GI bleeding. In the intent-to-treat population, clinically important gastric bleeding occurred in 3.9% of patients receiving omeprazole and in 5.5% of those receiving IV cimetidine.

Dosage and Administration

Administration

Omeprazole immediate-release and delayed-release capsules and omeprazole magnesium delayed-release tablets for self-administration are administered orally; oral suspensions of the drug are administered orally or through a gastric tube. To avoid decomposition of omeprazole in the acidic pH of the stomach, the commercially available delayed-release capsules and delayed-release oral suspension contain enteric-coated granules of the drug, and the immediate-release capsules and immediate-release oral suspension contain sodium bicarbonate.

Omeprazole immediate-release capsules (Zegerid) are administered orally and must be swallowed intact with water; other liquids should not be used. The capsules should not be opened and mixed with food. Both the 20- and 40-mg capsules contain the same amount of sodium bicarbonate (1100 mg). Therefore, two 20-mg capsules are not equivalent to and should not be substituted for one 40-mg capsule.

Patients should be advised that the delayed-release capsules must be swallowed intact and not chewed or crushed. However, for adult and pediatric patients with difficulty swallowing, the delayed-release capsule may be opened, the contents carefully emptied on and mixed with a tablespoon of applesauce in a bowl, and the mixture swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce should not be hot and should be soft enough to be swallowed without chewing. The applesauce and omeprazole enteric-coated pellet mixture should not be stored for future use. The manufacturer states that the 40-mg capsule, but not the 20-mg capsule, is bioequivalent when administered with or without applesauce. When the contents of a 20-mg capsule were administered with applesauce, the peak plasma omeprazole concentration decreased by 25%, but the area under the concentration-time curve (AUC) was not substantially changed. However, the clinical importance of this is unknown.

Tablets used for self-medication must be swallowed intact with a glass of water; the tablets should not be chewed or crushed and should not be crushed in food.

Omeprazole magnesium powder for delayed-release oral suspension (Prilosec) should be reconstituted prior to administration by pouring the contents of a single-dose packet containing 2.5 or 10 mg of the drug into a small cup containing 5 or 15 mL, respectively, of water. The suspension should be stirred well and allowed to thicken for 2-3 minutes. Within 30 minutes of preparation, the mixture should be stirred and consumed. If any material remains in the cup after the mixture is ingested, additional water should be added, mixed, and ingested immediately. If the delayed-release oral suspension is to be administered through a nasogastric or gastric tube, the contents of a 2.5- or 10-mg packet should be mixed with 5 or 15 mL of water, respectively, in a catheter-tipped syringe and then shaken immediately. The mixture should be allowed to thicken for 2-3 minutes. The mixture should be administered within 30 minutes of reconstitution; prior to administration, the syringe should be shaken again and the mixture injected into the stomach through the nasogastric or gastric tube (French size 6 or larger). The syringe should be refilled with additional water (5 or 15 mL, respectively), shaken, and used to flush any remaining drug mixture from the nasogastric or gastric tube into the stomach.

Omeprazole powder for immediate-release oral suspension (Zegerid) should be reconstituted prior to administration by pouring the contents of a single-dose packet containing 20 or 40 mg of the drug into a small cup containing 15-30 mL of water. The 20- and 40-mg powder for oral suspension packets contain the same amount of sodium bicarbonate (1680 mg). Therefore, two 20-mg packets are not equivalent to and should not be substituted for one 40-mg packet. The suspension should be stirred well and ingested immediately. The cup should be refilled with water and the contents ingested to ensure complete consumption of the dose. The manufacturer states that omeprazole powder for immediate-release oral suspension should not be mixed with any liquids (other than water) or foods. If the oral suspension is to be administered through a nasogastric or orogastric tube, the contents of each packet should be reconstituted with approximately 20 mL of water, stirred well and administered immediately. An appropriate-sized syringe should be used to instill the suspension into the tube. The suspension should then be flushed through the tube with 20 mL of water.

Following administration of delayed-release capsules of omeprazole with meals, the rate of GI absorption is reduced. Therefore, omeprazole should be taken before meals; administration up to 2 minutes prior to a meal reportedly has no adverse effect on oral bioavailability. However, since an acidic environment in the parietal cell canaliculi is required for conversion of proton-pump inhibitors (e.g., omeprazole) to their active sulfenamide metabolites, the American College of Gastroenterology suggests that proton-pump inhibitors are most effective when given about 30 minutes prior to meals; effectiveness may be compromised if these drugs are administered during the basal state (e.g., to fasting patients at bedtime) or concomitantly with other antisecretory agents (e.g., anticholinergics, histamine H2-receptor antagonists, somatostatin analogs, misoprostol). The manufacturer states that delayed-release preparations of omeprazole should be administered at least 1 hour before a meal. Antacids may be administered concomitantly with the delayed-release preparations of omeprazole.

The manufacturer states that immediate-release preparations of omeprazole (Zegerid) should be administered on an empty stomach at least 1 hour prior to a meal. For patients receiving continuous feedings via a nasogastric or orogastric tube, enteral feeding should be stopped temporarily for 3 hours before, and for 1 hour after administration of omeprazole immediate-release oral suspension. Also, the manufacturer states that antacids, antacid/alginic acid combinations, histamine H2-receptor antagonists, or histamine H2-receptor antagonist and antacid combinations may be used for ''breakthrough'' symptoms; however, efficacy of these agents for this use has not been established.

Omeprazole usually is administered once daily in the morning; however, administering the drug in divided doses (e.g., every 12 hours) has been reported to improve efficacy in patients receiving more than 80 mg daily.

Dosage

The manufacturer states that omeprazole dosage adjustments based on age are not necessary in geriatric patients. However, since the bioavailability of omeprazole appears to be increased substantially in Asians, the manufacturer states that dosage adjustment should be considered in Asian patients, especially when such patients are receiving long-term omeprazole therapy for maintenance of healing of erosive esophagitis. There is no evidence from the omeprazole prescription safety database that Asians experience excess risk from omeprazole, or that accumulation of omeprazole in the blood is harmful when used over a short period of time (e.g., 14 days of self-medication) in Asian patients.

Dosage of omeprazole magnesium is expressed in terms of omeprazole.

Duodenal Ulcer

For the short-term treatment of active duodenal ulcer, the usual adult dosage of omeprazole is 20 mg once daily. Therapy should be continued until healing occurs, usually within 2-4 weeks; some patients may benefit from an additional 4 weeks of therapy. Occasionally, dosages up to 40 mg daily may be necessary in patients who have been poorly responsive to therapy with H2-receptor antagonists.

When omeprazole is used in combination with clarithromycin (dual therapy) for the treatment of Helicobacter pylori infection in patients with active duodenal ulcer, the usual adult dosage of omeprazole is 40 mg once daily (in the morning) for 14 days. In patients who have an active ulcer present at the time anti-H. pylori therapy is initiated, an additional 14 days of therapy with omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief. When omeprazole is used in combination with clarithromycin and amoxicillin (triple therapy) for the treatment of H. pylori infection in patients with active duodenal ulcer, the usual adult dosage of omeprazole is 20 mg twice daily (morning and evening) for 10 days. In patients who have an active ulcer present at the time anti-H. pylori therapy is initiated, an additional 18 days of therapy with omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief. Multiple-drug regimens currently recommended by the American College of Gastroenterology (ACG) and many clinicians for the treatment of H. pylori infection consist of a proton-pump inhibitor (e.g., omeprazole) and 2 anti-infective agents (e.g., clarithromycin and amoxicillin or metronidazole) or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor; when omeprazole has been used in these regimens, dosages of 20 mg once daily to 80 mg twice daily (generally 20 mg twice daily) for 7-28 days have been used.While the minimum duration of therapy required to eradicate H. pylori infection with these 3- or 4-drug regimens has not been fully elucidated, the ACG and many clinicians state that treatment for longer than 1 week probably is not necessary. However, more prolonged therapy is recommended for patients with complicated, large, or refractory ulcers; therapy in such patients should be continued at least until successful eradication of H. pylori has been confirmed.

Gastric Ulcer

For the short-term treatment of active benign gastric ulcer, the usual adult dosage of omeprazole is 40 mg once daily for 4-8 weeks.

Gastroesophageal Reflux

For the short-term, symptomatic treatment of gastroesophageal reflux disease (GERD) without erosive esophageal lesions, the usual adult dosage of omeprazole is 20 mg once daily for 4 weeks. For the short-term treatment of erosive esophagitis, the usual adult dosage of omeprazole is 20 mg once daily for 4-8 weeks. Occasionally, dosages up to 40 mg daily may be necessary in some patients. Therapy is continued until healing occurs, usually within 4-8 weeks; an additional 4 weeks of therapy (up to 12 weeks for a single course) may contribute to healing and symptomatic improvement in some patients. If erosive esophagitis or symptomatic GERD (heartburn) recurs, the manufacturer states that additional 4- to 8-week courses of omeprazole may be considered. However, the American College of Gastroenterology (ACG) states that chronic, even lifelong, therapy with a proton-pump inhibitor is appropriate in many patients with GERD.

For maintenance therapy following healing of erosive esophagitis to reduce recurrence, the usual adult dosage of omeprazole is 20 mg daily. Safety and efficacy of omeprazole maintenance therapy for longer than 1 year have not been established.

For the treatment of symptomatic GERD or erosive esophagitis and for maintenance of healing of erosive esophagitis in pediatric patients 1-16 years of age, a dosage of 5 mg of omeprazole daily is recommended for pediatric patients weighing at least 5 kg but less than 10 kg, 10 mg daily is recommended for those weighing at least 10 kg but less than 20 kg, and 20 mg daily is recommended for those weighing 20 kg or more. Omeprazole was administered as a single daily dose for 4 weeks in one study of children with symptomatic nonerosive GERD. On a mg/kg basis, the dosage of omeprazole required to heal erosive esophagitis in pediatric patients is greater than that required in adults. In an uncontrolled open-label study, dosages of 0.7-3.5 mg/kg daily (up to a maximum dosage of 80 mg daily) for 3-6 months were required for healing in children 1-16 years of age; a dosage of 0.7 mg/kg daily resulted in healing of erosive esophagitis in 44% of children, but a dosage of 1.4 mg/kg daily was required for healing to occur in an additional 28% of the children. In an uncontrolled open-label study of 46 pediatric patients, dosages of omeprazole for maintenance therapy following healing of erosive esophagitis were half those required for initial healing in 54% of children, but the remainder required an increased dosage (0.7 to a maximum of 2.8 mg/kg daily) for all or part of the maintenance period; maintenance therapy was continued for about 2 years.

Self-Medication

For self-medication to relieve symptoms of frequent heartburn in adults 18 years of age or older, an omeprazole dosage of 20 mg once daily in the morning for 14 days is recommended. For self-medication, the manufacturer recommends that the dosage of omeprazole not exceed 20 mg in 24 hours. In addition, the drug should not be used for self-medication for longer than 14 days of continuous use and individuals should not exceed one course of therapy every 4 months unless otherwise directed by a clinician.

Pathologic GI Hypersecretory Conditions

For the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas, systemic mastocytosis), dosages of omeprazole should be individualized according to patient response and tolerance. The usual initial adult dosage is 60 mg (as delayed-release capsules or delayed-release oral suspension) once daily. Subsequent omeprazole dosage should be adjusted as tolerated and necessary to adequately suppress gastric acid secretion, and therapy continued as long as clinically necessary. Daily dosages exceeding 80 mg should be administered in divided doses.

Oral dosages ranging from 20 mg every other day to 360 mg daily (given in 3 divided doses) have been necessary to maintain basal gastric acid secretion at less than 10 mEq/hour in patients without a history of gastric surgery and less than 5 mEq/hour in those who have undergone gastric surgery; determination of gastric acid secretion during the hour prior to a dose may be useful in establishing optimum dosage. Omeprazole has been given continuously for more than 5 years in some patients with Zollinger-Ellison syndrome.

Upper GI Bleeding

For reduction of risk of upper GI bleeding in critically ill adults, the initial loading dose of omeprazole is 40 mg (as immediate-release oral suspension) followed by another 40-mg dose after 6-8 hours on the first day; thereafter, 40 mg (as immediate-release oral suspension) is administered once daily for up to 14 days. Safety and efficacy of omeprazole immediate-release oral suspension in critically ill patients for longer than 14 days have not been established.

Dosage in Renal and Hepatic Impairment

Although pharmacokinetics may be altered in patients with renal impairment, dosage adjustment does not appear necessary in patients with such impairment. However, the manufacturers state that dosage adjustment should be considered in patients with hepatic impairment, particularly in such patients receiving long-term omeprazole therapy for maintenance of healing of erosive esophagitis. Some clinicians recommend that such patients with hepatic dysfunction receiving dosages exceeding 20 mg daily should be monitored closely for possible adverse effects.

Cautions

Omeprazole generally is well tolerated. The most frequent adverse effects associated with omeprazole therapy involve the GI tract (e.g., diarrhea, nausea, constipation, abdominal pain, vomiting, flatulence) and the CNS (e.g., headache, dizziness). In short-term studies, the incidence of reported adverse effects was similar in patients receiving omeprazole or placebo. In addition, while the most common effects have been reported in 1-7% of patients receiving omeprazole, they were considered by investigators as being possibly, probably, or definitely related to the drug in only 0.2-2.4% of patients. Overall, the frequency and type of adverse effects produced by omeprazole appear to be similar to those produced by ranitidine, and the frequency of omeprazole-induced effects does not appear to be affected by age in adults. In dose-ranging studies, a relationship between doses ranging from 10-60 mg and the frequency of adverse effects was not observed. Adverse effects were severe enough to result in discontinuance of omeprazole therapy in less than 2% of patients in clinical studies. The manufacturer states that the adverse event profile of omeprazole in pediatric patients is similar to that in adults. However, the most frequently reported adverse effects in pediatric patients were respiratory effects, which were reported in about 75 or 18% of those 1-2 or 2-16 years of age, respectively; fever was frequently reported (33%) in children 1-2 years of age, and accidental injuries were frequently reported (about 4%) in those 2-16 years of age.

In controlled clinical trials with combined omeprazole-clarithromycin or omeprazole-clarithromycin-amoxicillin therapy, no adverse drug experiences peculiar to these combinations were noted.

In a controlled clinical trial, the adverse event profile was similar for critically ill patients receiving either omeprazole immediate-release suspension or IV cimetidine for up to 14 days. The most frequent adverse effects reported in patients receiving omeprazole were pyrexia (20.2%), hypokalemia (12.4%), nosocomial pneumonia (11.2%), hyperglycemia (10.7%), thrombocytopenia (10.1%), hypomagnesemia (10.1%), and hypotension (9.6%).

GI Effects

Diarrhea, abdominal pain, nausea, vomiting, constipation, flatulence, and acid regurgitation are the most frequent adverse GI effects reported with omeprazole therapy, occurring in about 1-5% of patients. Constipation, diarrhea, and gastric hypomotility occurred in 4.5, 3.9, and 1.7%, respectively, of critically ill patients receiving omeprazole immediate-release oral suspension or in 4.4, 8.3, and 3.3%, respectively, of those receiving IV cimetidine in a controlled clinical trial. Dysphagia, abdominal swelling, anorexia, irritable colon, fecal discoloration, pancreatitis (sometimes fatal), esophageal candidiasis, mucosal atrophy of the tongue, taste perversion, dry mouth, stomatitis, and microscopic colitis have been reported during postmarketing surveillance in patients receiving omeprazole; a causal relationship to the drug was not established in many cases. Benign gastric fundic polyps have been reported rarely and appear to resolve upon discontinuation of omeprazole therapy. Long-term administration of omeprazole has produced dose-related increases in gastric carcinoid tumors and enterochromaffin-like (ECL) cell hyperplasia in rats. Carcinoid tumors also have been observed in rats subjected to fundectomy or long-term treatment with other proton-pump inhibitors or high dosages of H2-receptor antagonists. Gastric biopsy specimens obtained from patients in long-term studies with omeprazole have demonstrated an increased frequency of ECL cell hyperplasia. However, no cases of ECL cell carcinoid tumor, dysplasia, or neoplasia were found.(See Cautions: Mutagenicity and Carcinogenicity.)

Adverse GI effects observed in controlled trials with combined omeprazole and clarithromycin therapy that were not reported with omeprazole monotherapy include taste perversion in 15% of such patients and tongue discoloration in 2%.

As with other agents that elevate intragastric pH, administration of omeprazole for 14 days in healthy individuals increased the intragastric concentration of viable bacteria. The pattern of bacteria isolated was similar to that of saliva. Alterations in the intragastric bacterial flora were reversible following discontinuance of omeprazole. Treatment with proton-pump inhibitors may result in a slight increase in the risk of GI infections caused by such organisms as Salmonella and Campylobacter species.

Available data suggest a possible association between use of proton-pump inhibitors and risk of Clostridium difficile infection, including C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis). In most observational studies to date, the risk of C. difficile infection in patients exposed to proton-pump inhibitors has ranged from 1.4-2.75 times that in patients not exposed to proton-pump inhibitors; however, some observational studies have found no increase in risk. Although many of the cases occurred in patients who had other risk factors for CDAD, including advanced age, comorbid conditions, and/or use of broad-spectrum anti-infectives, the US Food and Drug Administration (FDA) concluded that a contributory role for proton-pump inhibitors could not be definitively ruled out. The mechanism by which proton-pump inhibitors might increase the risk of CDAD has not been elucidated. Although it has been suggested that reduction of gastric acidity by gastric antisecretory agents might facilitate colonization with C. difficile, some studies have raised questions about this proposed mechanism or have suggested that the observed association is the result of confounding with other risk factors for CDAD. FDA also is reviewing the risk of CDAD in patients exposed to histamine H2-receptor antagonists.

CDAD can be serious in patients who have one or more risk factors for C. difficile infection and are receiving concomitant therapy with a proton-pump inhibitor; colectomy and, rarely, death have been reported. FDA recommends that patients receive proton-pump inhibitors at the lowest effective dosage and for the shortest possible time appropriate for their clinical condition. Patients experiencing persistent diarrhea should be evaluated for CDAD and should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Nervous System Effects

Headache and dizziness are the most common adverse nervous system effects of omeprazole, occurring in 6.9 and 1.5%, respectively, of patients in US clinical studies. In a controlled clinical trial in critically ill patients, agitation occurred in 3.4 or 8.8% of patients receiving omeprazole immediate-release oral suspension or IV cimetidine, respectively. Asthenia has been reported in 1.1-1.3% of patients receiving omeprazole; in controlled studies, the incidence of this effect was similar in patients receiving omeprazole, ranitidine, or placebo. Psychic and sleep disturbances, including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, and dream abnormalities, have been reported during postmarketing surveillance in patients receiving omeprazole; a causal relationship to the drug was not established in many cases. Other infrequent nervous system effects for which a causal relationship may not have been established include pain, fatigue, malaise, vertigo, paresthesia, and hemifacial dysesthesia.

Respiratory Effects

Upper respiratory tract infections and cough have occurred in 1.9 and 1.1%, respectively, of patients receiving omeprazole; in controlled studies, the incidence of these effects was similar in patients receiving omeprazole, ranitidine, or placebo. Acute respiratory distress syndrome, respiratory failure, and pneumothorax occurred in 3.4, 1.7, and 0.6%, respectively, of critically ill patients receiving omeprazole immediate-release oral suspension or in 3.9, 3.3, and 4.4%, respectively, of those receiving IV cimetidine in a controlled clinical trial. Epistaxis and pharyngeal pain have been reported during postmarketing surveillance in patients receiving omeprazole; a causal relationship to the drug was not established. Adverse respiratory effects have been reported in about 75% of children 1-2 years of age and in about 18% of those 2-16 years of age.

Other adverse respiratory effects observed in controlled trials with combined omeprazole and clarithromycin therapy that were not reported with omeprazole monotherapy were rhinitis in 2% of patients, pharyngitis in 1%, and flu syndrome in 1%.

Community-acquired Pneumonia

Administration of gastric antisecretory agents (e.g., proton-pump inhibitors, H2-receptor antagonists) has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia). A possible association between chronic administration of gastric acid-suppressive drugs and occurrence of community-acquired pneumonia has been evaluated using a large Dutch database (Integrated Primary Care Information [IPCI]) containing information on approximately 500,000 patients, 364,683 of whom (average follow-up: 2.7 years) were selected for evaluating any such association. During the 8-year population-based, case-control study, gastric acid suppressants were first prescribed in 19,459 individuals (12,337 received proton-pump inhibitors [mean duration of use: 5 months] and 10,177 received H2-receptor antagonists [mean duration of use: 2.8 months]; some individuals received both drugs). Most patients did not undergo endoscopy and were treated empirically for upper GI symptoms. In this study, first occurrence of pneumonia (confirmed by radiography or microbiologic testing in 18% of patients) was reported in 5551 individuals; development of pneumonia occurred in 185 individuals while receiving gastric acid suppressants and in 292 individuals who had discontinued such use.

The adjusted relative risk for development of pneumonia (or the incidence rate) was 0.6, 2.3 and 2.5 per 100 person-years for individuals not receiving acid-suppressive drugs, for those receiving H2-receptor antagonists, and for those receiving proton-pump inhibitors, respectively. Patients using gastric acid suppressants developed community-acquired pneumonia 4.5 (95% confidence interval of 3.8-5.1) times more often than those who never used such drugs. When evaluating use of all gastric acid suppressants, current use of the drugs was associated with a small (27%) overall increase in the risk of pneumonia (adjusted odds ratio 1.27 and 95% confidence interval of 1.06-1.54). Higher risks were observed for current users of proton-pump inhibitors and H2-receptor antagonists; the adjusted relative risk for developing community-acquired pneumonia was 1.89 (95% confidence interval of 1.36-2.62) or 1.63 (95% confidence interval of 1.07-2.48), respectively, for these classes of drugs compared with those who discontinued using these agents. Estimates for developing pneumonia were higher (2.2 [95% confidence interval of 1.4-3.5] for proton-pump inhibitors and 1.7 [95% confidence interval of 0.8-2.9] for H2-receptor antagonists) when only laboratory-confirmed cases of pneumonia were considered for analysis.

Although there was variation among individual proton-pump inhibitors and individual H2-receptor antagonists, the numbers were small and the heterogeneity was not considered significant. For patients currently receiving proton-pump inhibitors, a dose-response relationship for developing pneumonia was observed; individuals using more than one defined daily dose of these drugs had a 2.3-fold increased risk for developing pneumonia compared with those who discontinued gastric acid suppressants. Such a dose-response relationship for developing pneumonia was not observed in patients receiving H2-receptor antagonists; however, dose variation of these drugs was limited. Among current users of proton-pump inhibitors or H2-receptor antagonists, the risk for developing pneumonia was most pronounced among those who initiated such therapies within the past 30 days.

Although the exact mechanism for development of community-acquired pneumonia in patients receiving gastric acid suppressants has not been fully elucidated, it has been suggested that reduction of gastric acid secretion by acid suppressive therapy and consequent increases of gastric pH may result in a favorable environment for the development of infection. Intragastric acidity constitutes a major nonspecific defense mechanism of the stomach to ingested pathogens; when gastric pH is less than 4, most pathogens are killed, while at higher gastric pH, pathogens may survive. Since intragastric pH should be maintained above 4 for several hours for the effective management of upper GI symptoms, acid suppressive therapy may lead to insufficient elimination or even increased colonization of ingested pathogens. Some evidence indicates that acid-suppressive therapy may result in nosocomial infections.

It should be considered that certain patients (e.g., those with pleuritic chest pain, hypothermia, systolic hypotension, tachypnea, diabetes mellitus, neoplastic disease, neurologic disease, bacteremia, leukopenia, multilobar pulmonary infiltrate) are at increased risk for developing infections and in these individuals community-acquired pneumonia may be associated with increased mortality. Some clinicians state that gastric acid-suppressive drugs should be used in patients in whom community-acquired pneumonia may be severe (e.g., those with asthma or chronic obstructive lung disease, immunocompromised patients, pediatric or geriatric individuals) only when clearly needed and the lowest effective dose should be employed.

Musculoskeletal Effects

Back pain has been reported in about 1% of patients receiving omeprazole. Other musculoskeletal effects have been reported during postmarketing surveillance; a causal relationship to the drug was not established in many cases. Such effects include muscle cramps, myalgia, muscle weakness, joint pain, and leg pain. Bone fracture also has been reported during postmarketing surveillance in patients receiving omeprazole.

Findings from several observational studies suggest that therapy with proton-pump inhibitors, particularly in high dosages (i.e., multiple daily doses) and/or for prolonged periods of time (i.e., one year or longer), may be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine. The magnitude of the risk is not clear. To date, most of the observational studies assessing fracture risk in patients receiving proton-pump inhibitor therapy have limited the study population to individuals at least 50 years of age or older. Some of the studies found that the risk of hip fracture was increased with use of higher dosages of the drugs (e.g., average dosage of at least 1.5 ''pills'' daily) or with long-term use of the drugs, particularly long-term use of high dosages (e.g., dosages exceeding 1.75 times the average daily dosage for more than one year). Study results relating duration of proton-pump inhibitor use to emergence of increased fracture risk have been variable; one study found an increased risk of hip fracture after more than one year of use, whereas another study found an increased risk of hip fracture or osteoporosis-related fracture after 5 or 7 years of use, respectively. In yet another study, an increased risk of hip or spinal fracture was observed when the drugs were last used within the previous year but not when last use was more distant. One study that excluded patients with major risk factors for hip fracture found no relationship between proton-pump inhibitor use and hip fracture occurrence. Because these observational studies relied extensively on claims data from computerized administrative databases, the clinical relevance of reported findings is difficult to determine. FDA states that a causal relationship between proton-pump inhibitor use and fracture occurrence has not been established. To further evaluate this safety issue, FDA intends to analyze data obtained from several large, long-term, placebo-controlled trials of bisphosphonates in women at risk for osteoporosis-related fractures to assess risk of fractures based on use or nonuse of proton-pump inhibitors.

The mechanism by which proton-pump inhibitors may increase risk of fractures has not been elucidated, but it has been suggested that the mechanism may involve decreased insoluble calcium absorption secondary to increased gastric pH. Results of 3 observational studies showed no consistent relationship between proton-pump inhibitor use and bone mineral density. Additional studies evaluating effects of these drugs on bone homeostasis, including effects on biomarkers of bone formation and resorption, are ongoing.

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients receiving long-term therapy (for at least 3 months or, in most cases, for longer than one year) with proton-pump inhibitors, including omeprazole.(See Cautions: Precautions and Contraindications.) On March 2, 2011, after reviewing reports of hypomagnesemia in patients receiving proton-pump inhibitors (i.e., 38 cases from the Adverse Event Reporting System [AERS] database, 23 cases from the medical literature [at least 8 of which have been identified in AERS]), FDA confirmed that long-term use (in most cases, longer than one year) of proton-pump inhibitors may be associated with an increased risk of hypomagnesemia; the incidence of this adverse effect could not be quantified because hypomagnesemia is likely underrecognized and underreported. The mechanism responsible for hypomagnesemia associated with long-term use of proton-pump inhibitors is unknown; however, long-term use of these agents may be associated with changes in intestinal absorption of magnesium.

Clinically serious adverse effects associated with hypomagnesemia, which are similar to manifestations of hypocalcemia, include tetany, seizures, tremors, carpopedal spasm, arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia), and abnormal QT interval. Other reported adverse effects include paresthesia, muscle weakness, muscle cramps, lethargy, fatigue, and unsteadiness. Manifestations of hypomagnesemia secondary to proton-pump inhibitor therapy may not be present in all patients. Hypomagnesemia also produces impaired parathyroid hormone secretion, which may lead to hypocalcemia. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuance of the proton-pump inhibitor. Following discontinuance of the proton-pump inhibitor, hypomagnesemia resolved within a median of one week; upon rechallenge, hypomagnesemia recurred within a median of 2 weeks. In a few patients in whom reinitiation of proton-pump inhibitor therapy was necessary, use of pantoprazole, the least potent proton-pump inhibitor, in combination with oral magnesium supplements resulted in acceptable control of GI discomfort (e.g., dyspepsia, reflux symptoms) without causing recurrent hypomagnesemia; further study is needed to establish the role, if any, of pantoprazole in patients with proton-pump inhibitor-induced hypomagnesemia.

Because nonprescription (over-the-counter, OTC) proton-pump inhibitors are marketed at low dosages and are only intended for a 14-day course of treatment up to 3 times per year, FDA states that there is very little risk of hypomagnesemia when these preparations are used in accordance with the directions on the labeling.

Hepatic Effects

Mild and, rarely, marked increases in serum ALT (SGPT), AST (SGOT), γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP), alkaline phosphatase, and bilirubin concentrations have been reported during postmarketing surveillance in patients receiving omeprazole, but in many cases a causal relationship has not been established. In a controlled clinical trial in critically ill patients, abnormal liver function test results (not otherwise specified) occurred in 1.7 or 3.3% of patients receiving omeprazole immediate-release oral suspension or IV cimetidine, respectively. Rare occurrences of symptomatic liver disease have been reported, including hepatocellular, cholestatic, or mixed hepatitis, jaundice, liver necrosis, hepatic failure, and hepatic encephalopathy. Fatalities have been reported in some patients with hepatic failure or liver necrosis.

Dermatologic and Sensitivity Reactions

In a controlled clinical trial in critically ill patients, rash and decubitus ulcer occurred in 5.6 and 3.4%, respectively, of patients receiving omeprazole immediate-release oral suspension or in 6.1 and 2.8%, respectively, of those receiving IV cimetidine.

Rash has been reported during postmarketing surveillance in patients receiving omeprazole; severe generalized reactions such as toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, and lichenoid eruptions have been reported. Other adverse dermatologic effects reported during postmarketing surveillance include skin inflammation, urticaria, purpura and/or petechiae (some cases with rechallenge) angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis. Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria, have been reported with omeprazole therapy. In many cases, a causal relationship to omeprazole has not been established.

Hematologic Effects

Short-term use of omeprazole does not appear to be associated with substantial changes in hematologic parameters. However, in a controlled clinical trial of critically ill patients, thrombocytopenia, anemia, and aggravated anemia occurred in 10.1, 7.9 and 2.2%, respectively, of those receiving omeprazole immediate-release oral suspension, or in 6.1, 7.7, and 3.9%, respectively, of those receiving IV cimetidine. Agranulocytosis (occasionally fatal) has been reported rarely with omeprazole therapy, but a causal relationship to the drug is uncertain. Other adverse hematologic effects reported during postmarketing surveillance include pancytopenia, thrombocytopenia, neutropenia, leukopenia, anemia, and leukocytosis. Hemolytic anemia has been reported rarely in patients receiving omeprazole. In many cases, a causal relationship with omeprazole has not been established.

Genitourinary Effects

Acute interstitial nephritis (some cases with positive rechallenge), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine concentration, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia have been reported during postmarketing surveillance in patients receiving omeprazole; in many cases a causal relationship to the drug has not been established. Sexual disturbances (e.g., priapism) have been reported occasionally in patients receiving omeprazole.

Cardiovascular Effects

In a controlled clinical trial of critically ill patients, hypotension and hypertension occurred in 9.6 and 7.9%, respectively, of patients receiving omeprazole immediate-release oral suspension, or in 6.6 and 3.3%, respectively, of those receiving IV cimetidine. Atrial fibrillation, ventricular tachycardia, bradycardia, supraventricular tachycardia and tachycardia (not otherwise specified) occurred in 6.2, 4.5, 3.9, 3.4, and 3.4%, respectively, of patients receiving omeprazole or in 3.9, 3.3, 2.8, 1.1, and 3.3%, respectively, of patients receiving IV cimetidine.

Chest pain, angina pectoris, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema have been reported during postmarketing surveillance in patients receiving omeprazole; a causal relationship to the drug has not been established in many cases.

Although preliminary safety data from 2 long-term clinical trials comparing omeprazole or esomeprazole with antireflux surgery in patients with severe gastroesophageal reflux disease (GERD) raised concerns about a potential increased risk of cardiac events (myocardial infarction, heart failure, and sudden death) in patients receiving these drugs, FDA has reviewed safety data from these and other studies of the drugs and has concluded that long-term use of omeprazole or esomeprazole is not likely to be associated with an increased risk of such cardiac events. FDA has concluded that the apparent increase in cardiac events observed in the early analyses is not a true effect of the drugs.

In one study (a 14-year study comparing omeprazole with antireflux surgery in 298 patients), death from cardiac causes (heart failure, sudden death) or nonfatal myocardial infarction occurred in 8 or 9 patients, respectively, randomized to receive omeprazole and in 2 or 2 patients, respectively, randomized to undergo surgery. However, the findings may have been biased by baseline differences between the 2 groups, since patients in the surgery group tended to be younger and healthier and were less likely to have a history of myocardial infarction than those receiving omeprazole. In addition, some patients withdrew from the study prior to undergoing surgery, and several underwent surgery and also received drug therapy. Fewer than half of the patients remained in the study until its completion. Preliminary data from the second study (an ongoing study comparing esomeprazole with antireflux surgery in 554 patients) also suggested a difference in occurrence of cardiac events between treatment groups; however, after 5 years of follow-up, a similar number of patients in each treatment group had experienced cardiac-related events. FDA reviewed safety data from 14 additional comparative studies of omeprazole (including 4 placebo-controlled studies) and indicated that these studies do not suggest that omeprazole is associated with an increased risk of cardiac events. None of the studies were designed to assess cardiac risk, and patient follow-up in the studies was incomplete.

Ocular Effects

Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis, and double vision have been reported during postmarketing surveillance in patients receiving omeprazole; in many cases a causal relationship to the drug has not been established.

Other Adverse Effects

In a controlled clinical trial of critically ill patients, hypophosphatemia, hypocalcemia, fluid overload, and hyponatremia occurred in 6.2, 6.2, 5.1, and 3.9%, respectively, of patients receiving omeprazole immediate-release oral suspension or in 3.9, 5.5, 7.7, and 2.8%, respectively, of patients receiving IV cimetidine. Hypoglycemia, hyperkalemia, and hypernatremia occurred in 3.4, 2.2, and 1.7%, respectively, of those receiving omeprazole or in 4.4, 3.3, and 5%, respectively, of patients receiving IV cimetidine. Hyperpyrexia and edema occurred in 4.5 and 2.8%, respectively, of patients receiving omeprazole or in 1.7 and 6.1%, respectively, of patients receiving IV cimetidine. Sepsis (not otherwise specified), oral candidiasis, urinary tract infection, and candidal infection (not otherwise specified) occurred in 5.1, 3.9, 2.2, and 1.7%, respectively, of patients receiving omeprazole or in 5, 0.6, 3.3, and 3.9%, respectively, of patients receiving IV cimetidine.

Hyponatremia, hypoglycemia, weight gain, fever, and tinnitus have been reported during postmarketing surveillance in patients receiving omeprazole, but in many cases were not attributed to the drug. Acute gout also has been reported during omeprazole therapy.

Accidental injury occurred in about 4% of pediatric patients 2-16 years of age receiving omeprazole in clinical studies.

Limited evidence suggests that omeprazole therapy may cause a dose-dependent reduction in cyanocobalamin absorption, although conflicting data also exist. In one study, absorption of protein-bound cyanocobalamin decreased from a median value of 2.2 or 2.3% at baseline to 0.8 or 0.5% in healthy men receiving 20 or 40 mg, respectively, of omeprazole daily for 2 weeks.(See Cautions: Precautions and Contraindications.)

Precautions and Contraindications

Symptomatic response to omeprazole should not be interpreted as precluding the presence of gastric malignancy.

While available endoscopic and histologic examinations of gastric biopsy specimens from humans exposed short-term to omeprazole have failed to reveal any associated risk, a dose-related increase in gastric carcinoid tumors has been observed during long-term exposure in animals, and further data from humans are needed to rule out the possibility of an increased risk of tumors during long-term exposure to the drug.(See Cautions: Mutagenicity and Carcinogenicity.)

Atrophic gastritis occasionally has been noted in gastric corpus biopsies from patients receiving long-term treatment with omeprazole.

The possibility that gastric acid-suppressive therapy may increase the risk of community-acquired pneumonia should be considered. (See Respiratory Effects: Community-acquired Pneumonia, in Cautions.)

Findings from several observational studies suggest that therapy with proton-pump inhibitors, particularly in high dosages and/or for prolonged periods of time, may be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.(See Cautions: Musculoskeletal Effects.) Although controlled studies are required to confirm these findings, patients should receive proton-pump inhibitors at the lowest effective dosage and for the shortest possible time appropriate for their clinical condition. Individuals using omeprazole for self-medication should be advised that they should use the drug only as directed for no longer than 14 days of continuous use and that they should not exceed one course of therapy every 4 months. Patients who are at risk for osteoporosis-related fractures should receive an adequate intake of calcium and vitamin D and should have their bone health assessed and managed according to current standards of care.

Long-term use (in most cases, longer than one year) of proton-pump inhibitors may be associated with an increased risk of hypomagnesemia. In patients expected to receive long-term therapy with a proton-pump inhibitor or in those receiving a proton-pump inhibitor concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), clinicians should consider measurement of serum magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter. Patients receiving proton-pump inhibitors should be advised to seek immediate care if manifestations of hypomagnesemia (e.g., arrhythmias, tetany, tremor, seizures) occur; in children, abnormal heart rates may cause fatigue, upset stomach, dizziness, and lightheadedness. Patients receiving nonprescription proton-pump inhibitors should be advised to follow the manufacturer's directions on the package carefully; if therapy with a nonprescription proton-pump inhibitor is continued for longer than the maximum recommended duration (an unlabeled [off-label] use), patients should be informed of the potential increased risk of hypomagnesemia.

Although preliminary safety data from 2 long-term clinical trials comparing omeprazole or esomeprazole with antireflux surgery in patients with severe gastroesophageal reflux disease (GERD) raised concerns about a potential increased risk of cardiac events (myocardial infarction, heart failure, and sudden death) in patients receiving these drugs, FDA has reviewed safety data from these and other studies of the drugs and has concluded that long-term use of omeprazole or esomeprazole is not likely to be associated with an increased risk of such cardiac events. FDA has concluded that the apparent increase in cardiac events observed in the early analyses is not a true effect of the drugs and recommends that clinicians continue to prescribe and patients continue to use these drugs in the manner described in the manufacturers' labelings.(See Cautions: Cardiovascular Effects.)

Because available data suggest a possible association between use of proton-pump inhibitors and risk of Clostridium difficile infection, patients should be advised to contact a clinician if persistent watery stools, abdominal pain, and fever occur.

Limited data suggest that omeprazole therapy may cause a dose-dependent reduction in cyanocobalamin absorption.(See Cautions: Other Adverse Effects.) Whether such a reduction in cyanocobalamin absorption can result in a deficiency of the vitamin has not been determined, although it has been suggested that pending further study, serum cyanocobalamin concentrations should be monitored in patients receiving long-term therapy with omeprazole.

Increases in intragastric pH may result in hypergastrinemia, enterochromaffin-like cell hyperplasia, and increased serum chromogranin A (CgA) concentrations. Increased CgA concentrations may produce false-positive results for diagnostic tests for neuroendocrine tumors. Clinicians should temporarily discontinue omeprazole therapy before assessing CgA concentrations and consider repeating the test if initial CgA concentrations are high.

Each 20- or 40-mg packet of omeprazole powder for immediate-release oral suspension (Zegerid) contains 1680 mg of sodium bicarbonate (460 mg [20 mEq] of sodium). Each 20- or 40-mg immediate-release capsule of omeprazole (Zegerid) contains 1100 mg of sodium bicarbonate (304 mg [13 mEq] of sodium). The sodium content of these preparations should be taken into consideration in patients whose sodium intake must be restricted; increased sodium intake may produce edema and weight increase. Sodium bicarbonate may cause metabolic alkalosis, seizures, and tetany, and chronic use with calcium or milk may cause milk-alkali syndrome. Acute toxicity associated with sodium bicarbonate overdose may include hypocalcemia, hypokalemia, hypernatremia, and seizures. Sodium bicarbonate should be used with caution in patients with Bartter's syndrome, hypokalemia, respiratory alkalosis, or acid-base abnormalities. Sodium bicarbonate is contraindicated in patients with metabolic alkalosis or hypocalcemia.

In clinical trials in patients who received combined clarithromycin-omeprazole therapy for H. pylori infection, some H. pylori isolates demonstrated an increase in clarithromycin MICs over time, indicating decreased susceptibility and increasing resistance to the drug. Susceptibility testing should be performed if possible in patients with H. pylori infection in whom therapy with combined clarithromycin-omeprazole fails (i.e., as determined in clinical trials by a positive result for H. pylori on culture or histologic testing 4 weeks following completion of therapy); if resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative anti-infective therapy should be instituted. The American College of Gastroenterology (ACG) states that clarithromycin or metronidazole should not be used subsequently in patients with H. pylori infection who fail therapy that includes these drugs since resistance consistently emerges during such unsuccessful therapy.

Patients should be advised to consult their clinician before using omeprazole for self-medication if they are taking warfarin, an antifungal agent (e.g., ketoconazole), diazepam, or digoxin. Patients with heartburn that has persisted for more than 3 months or heartburn in conjunction with lightheadedness, sweating, or dizziness should consult their clinician before using omeprazole for self-medication. Patients should be advised to consult their clinician before using omeprazole for self-medication if they are experiencing chest or shoulder pain with lightheadedness, shortness of breath, sweating, or pain spreading to arms, neck, or shoulders. Those with frequent chest pain, unexplained weight loss, nausea and vomiting, stomach pain, or frequent wheezing (especially with heartburn) also should consult their clinician before using omeprazole for self-medication. Patients should discontinue taking omeprazole for self-medication and consult their clinician if heartburn persists, or worsens after 14 days of therapy, or a course of treatment is needed more frequently than every 4 months. Patients with difficulty or pain with swallowing, vomiting with blood, or bloody or blackened stools should not use omeprazole for self-medication; such manifestations should be reported promptly to a clinician, since they may be indicative of a serious condition requiring alternative treatment. Women who are pregnant or breast feeding should consult their clinician before using omeprazole for self-medication.

Omeprazole is contraindicated in patients with known hypersensitivity to the drug, esomeprazole, or other substituted benzimidazoles (e.g., lansoprazole, pantoprazole, rabeprazole), or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of omeprazole (omeprazole delayed-release capsules and omeprazole magnesium delayed-release oral suspension) have been established for the treatment of symptomatic gastroesophageal reflux disease (GERD), erosive esophagitis, and maintenance of healing of erosive esophagitis in pediatric patients 1-16 years of age. Use in pediatric patients is supported by adequate and well-controlled studies in adults and additional pharmacokinetic data and clinical and safety studies in children.(See Gastroesophageal Reflux: Clinical Trials and see Gastroesophageal Reflux: Maintenance Therapy, in Uses.)

Safety and efficacy of omeprazole in pediatric patients younger than 1 year of age have not been established. Safety and efficacy of omeprazole for self-medication in those younger than 18 years of age have not been established. Safety and efficacy of omeprazole immediate-release capsules and oral suspension (Zegerid) have not been established in pediatric patients younger than 18 years of age.

Geriatric Precautions

In US and European clinical trials, more than 2000 patients treated with omeprazole were 65 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Although elimination of omeprazole may be somewhat delayed and oral bioavailability increased in the elderly, clinically important differences in the pharmacokinetic profile of omeprazole between geriatric individuals and younger adults generally do not appear to exist. Therefore, dosage adjustment solely on the basis of age generally is not required for geriatric patients.

The adverse effect profile of omeprazole is similar in geriatric patients and those 65 years of age and younger.

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was observed in vivo in the rat liver DNA damage assay or in some in vitro test systems, including the microbial (Ames test) and mammalian (mouse lymphoma) assays. Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosome aberration assay, in 1 of 2 in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay.

In animals, long-term administration of relatively high dosages of omeprazole results in morphologic changes in the gastric mucosa. Such changes observed in rats during long-term (24-month) administration of the drug include dose-related increases in gastric carcinoid tumors and enterochromaffin-like (ECL) cell hyperplasia, which are thought to represent exaggerated physiologic responses occurring secondary to profound inhibition of gastric acid secretion and subsequent hypergastrinemia and reversible hypertrophy of oxyntic mucosa. While such changes have not been observed following short-term administration of the drug in humans, additional long-term data are needed to rule out the possibility of an increased risk of gastric tumors in patients receiving long-term omeprazole therapy. In two 24-month studies in rats given omeprazole dosages of 1.7, 3.4, 13.8, 44, and 140.8 mg/kg daily (about 0.7-57 times the human dosage of 20 mg daily based on body surface area), the drug caused a dose-related increase in gastric ECL cell carcinoids in both male and female rats; the increase in carcinoids occurred more frequently in female rats. In addition, ECL cell hyperplasia was observed in both male and female rats receiving omeprazole. In female rats given omeprazole dosages of 13.8 mg/kg daily (about 6 times the human dosage of 20 mg daily based on body surface area) for 1 year and then observed for another year without the drug, carcinoids were not detected but ECL hyperplasia occurred in 94% of rats given omeprazole versus 10% of controls at the end of 1 year; at the end of the second year, hyperplasia was observed in 46% of rats given omeprazole versus 26% of controls. Gastric adenocarcinoma was reported in one rat; similar tumors were not seen in male or female rats treated for 2 years. For this strain of rat no similar tumor had been noted historically, but the finding of this tumor in only one rat is difficult to interpret. In a 1-year toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males (but not in females) given omeprazole at dosage levels of 0.4, 2, and 16 mg/kg daily (about 0.2-6.5 times the human dosage of 20 mg daily based on body surface area). In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at 140.8 mg/kg daily (about 57 times the human dosage of 20 mg daily based on body surface area). Long-term carcinogenicity studies (78 weeks) in mice did not demonstrate increased tumor occurrence; however, the manufacturer states that the study was inconclusive. The drug was not carcinogenic in a 26-week p53+/- transgenic mouse study.

A number of patients with Zollinger-Ellison syndrome receiving long-term therapy with omeprazole have developed gastric carcinoids; however, Zollinger-Ellison syndrome is known to be associated with such tumors, and these findings are believed to be related to the underlying disease rather than to omeprazole therapy. Gastric corpus biopsy specimens obtained from more than 3000 patients in long-term studies with omeprazole have demonstrated an increased frequency of ECL cell hyperplasia (including micronodular hyperplasia of argyrophil cells) in association with increased plasma gastrin concentrations and progression to subatrophic or atrophic gastritis. However, no evidence of ECL cell carcinoids, dysplasia, or neoplasia has been observed in these patients, and it has been suggested that the development of mucosal cell hyperplasia may be related to the severity and natural progression of gastritis rather than to hypergastrinemia.

Pregnancy, Fertility, and Lactation

Pregnancy

Omeprazole crosses the placenta in animals and in humans. Reproductive studies in rats or rabbits using omeprazole dosages up to 138 or 69 mg/kg daily (about 56 times the human dosage of 20 mg daily based on body surface area), respectively, have not revealed evidence of teratogenicity. However, in rabbits given omeprazole dosages of 6.9-69.1 mg/kg daily (about 5.6-56 times the human dosage of 20 mg daily based on body surface area), dose-related increases in embryolethality, fetal resorptions, and pregnancy loss occurred. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from administration of omeprazole in dosages of 13.8-138 mg/kg daily (about 5.6-56 times the human dosage of 20 mg daily based on body surface area) to parents.

There are no adequate and controlled studies using omeprazole in pregnant women. Most reported experience with omeprazole during human pregnancy has been first trimester exposure; duration of use (i.e., intermittent, long-term) rarely has been specified. A review of published data (considered fair in quality and quantity) by the Teratogen Information System (TERIS) concluded that therapeutic dosages of omeprazole during pregnancy are unlikely to pose a substantial teratogenic risk. Data from cohort studies have not demonstrated that omeprazole exposure is associated with a statistically significant increase in the rate of major birth defects; however, the studies lacked the power to detect small increases in birth defects or in rare malformations. Therefore, additional study is needed.

A population-based retrospective cohort epidemiologic study using data from the Swedish Medical Birth Registry reported on outcomes in infants whose mothers used omeprazole during pregnancy; most (about 86%) were exposed to omeprazole during the first trimester, 4% during and beyond the first trimester, and about 10% were exposed only after the first trimester of pregnancy. Exposure to omeprazole was not associated with increased risk of any malformation (odds ratio 0.82 and 95% confidence interval of 0.50-1.34), low birth weight, or low Apgar score. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in the normal population, but both effects may be random. In an earlier study using data from the Swedish Medical Birth Registry, exposure to proton-pump inhibitors was not associated with increased risk of congenital malformation.

In a retrospective cohort study, the incidence of congenital malformations in women who received omeprazole or histamine H2-antagonists (cimetidine or ranitidine) in the first trimester of pregnancy was compared with a control group of women who were not exposed to acid-suppressant drugs. The overall malformation rate was 4.4% (95% confidence interval of 3.6-5.3), the malformation rate for nonexposed women was 3.8% (95% confidence interval of 3-4.9), and the malformation rate associated with omeprazole exposure was 3.6% (95% confidence interval of 1.5-8.1). The relative risk of malformations associated with first-trimester exposure to omeprazole (compared with nonexposed women) was 0.9 (95% confidence interval of 0.3-2.2). The study could effectively rule out a relative risk greater than 2.5 for all malformations. Rates of preterm delivery or growth retardation did not differ between the groups.

A controlled prospective observational study followed women exposed to omeprazole, disease-paired controls exposed to histamine H2-receptor antagonists, and controls exposed to nonteratogenic agents (e.g., acetaminophen, dental radiation) during pregnancy; major congenital malformations occurred in 4, 2.8, and 2%, respectively, of live births, or in 5.1%, 3.1%, and 3%, respectively, of live births when exposure occurred during the first trimester of pregnancy. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight did not differ between the groups. The study lacked statistical power to detect a small increase in major malformations; the sample size had 80% power to detect a fivefold increase in the major malformation rate.

The manufacturers state that several studies reported that adverse short-term effects were not observed in infants when a single oral or IV dose of omeprazole was administered to pregnant women as premedication for cesarean section under general anesthesia.

Omeprazole immediate-release capsules and oral suspension contain sodium bicarbonate; chronic use of sodium bicarbonate may lead to systemic alkalosis, and increased sodium intake may produce edema and weight increase.

Because there are no adequate and controlled studies using omeprazole in pregnant women, and because studies to date in animals and pregnant women cannot rule out the possibility of harm, the drug should be used during pregnancy only when clearly needed and only when the potential benefits justify the possible risk to the fetus.

Fertility

Reproductive studies in rats using omeprazole dosages of up to 138 mg/kg daily (about 56 times the human dose of 20 mg daily based on body surface area) have not revealed evidence of impaired fertility.

Lactation

Omeprazole is distributed into human milk; following oral administration of omeprazole 20 mg in one lactating woman, the peak concentration of the drug in breast milk was less than 7% of the peak serum concentration. Because of the potential for serious adverse reactions to omeprazole in nursing infants, and because of the potential for tumorigenicity shown in animal studies, a decision should be made whether to discontinue nursing or the drug, taking account the importance of the drug to the woman. In addition, omeprazole immediate-release capsules and oral suspension contain sodium bicarbonate, which should be used with caution in nursing mothers.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Omeprazole can prolong the elimination of diazepam, warfarin (the R-isomer), phenytoin, cyclosporine, disulfiram, and benzodiazepines, and the possibility that dosages of these and other drugs that are metabolized by cytochrome P-450 (CYP)-mediated oxidation in the liver may require adjustment should be considered when concomitant omeprazole therapy is initiated or discontinued.

Omeprazole is extensively metabolized by the CYP enzyme system. Drugs that induce CYP2C19 or CYP3A4 (e.g., rifampin, St. John's wort [Hypericum perforatum]) can substantially decrease omeprazole concentrations. In a crossover study, concomitant use of omeprazole and St. John's wort (300 mg 3 times daily for 14 days) in healthy men resulted in decreased exposure to omeprazole; peak plasma concentrations and area under the concentration-time curve (AUC) of omeprazole were decreased by 37.5 and 37.9%, respectively, in poor CYP2C19 metabolizers and by 49.6 and 43.9%, respectively, in extensive metabolizers. Concomitant use of omeprazole with St. John's wort or rifampin should be avoided.

Drugs that Cause Hypomagnesemia

In patients receiving diuretics (i.e., loop or thiazide diuretics) or other drugs that may cause hypomagnesemia, monitoring of magnesium concentrations should be considered prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.(See Cautions: Hypomagnesemia.)

Gastric pH-dependent Drugs

The possibility that omeprazole-induced increases in gastric pH may affect the bioavailability of drugs such as ketoconazole, ampicillin esters, iron salts, erlotinib, or digoxin (where gastric acidity is an important determinant in oral absorption) should be considered. Concomitant use of omeprazole 20 mg once daily and digoxin in healthy individuals increased digoxin bioavailability by 10% (up to 30% in some individuals); monitoring for manifestations of digoxin toxicity may be required when omeprazole is used concomitantly.

Antiretroviral Agents

Atazanavir

Concomitant use of omeprazole 40 mg once daily and atazanavir (with or without low-dose ritonavir) results in a substantial decrease in plasma concentrations of atazanavir and possible loss of the therapeutic effect of the antiretroviral agent. The manufacturers of omeprazole state that concomitant use of omeprazole with atazanavir is not recommended. If atazanavir is administered in an antiretroviral treatment-naive patient receiving a proton-pump inhibitor, a ritonavir-boosted regimen of 300 mg of atazanavir once daily with ritonavir 100 mg once daily with food is recommended. The dose of the proton-pump inhibitor should be administered approximately 12 hours before ritonavir-boosted atazanavir; the dose of the proton-pump inhibitor should not exceed omeprazole 20 mg daily (or equivalent). Concomitant use of proton-pump inhibitors with atazanavir is not recommended in antiretroviral treatment-experienced patients.

Darunavir

Concomitant use of omeprazole with ritonavir-boosted darunavir resulted in decreased plasma concentrations of omeprazole; plasma concentrations of darunavir were not affected. However, no dosage adjustment of either drug is required when omeprazole is used concomitantly with ritonavir-boosted darunavir.

Fosamprenavir

Concomitant use of esomeprazole and fosamprenavir increased the AUC of esomeprazole by about 55% but did not substantially alter plasma concentrations of amprenavir (active metabolite of fosamprenavir). Concomitant use of esomeprazole and ritonavir-boosted fosamprenavir did not substantially affect concentrations of either amprenavir or esomeprazole. No dosage adjustment is required when proton-pump inhibitors are used concomitantly with fosamprenavir (with or without ritonavir).

Lopinavir

Concomitant use of omeprazole with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) did not have a clinically important effect on plasma concentrations or AUC of lopinavir. No dosage adjustment is required when proton-pump inhibitors are used concomitantly with lopinavir/ritonavir.

Nelfinavir

Concomitant use of omeprazole 40 mg once daily (given 30 minutes before a nelfinavir dose) and nelfinavir 1.25 g twice daily decreased peak plasma concentrations and AUCs of nelfinavir by 37 and 36%, respectively, and of its major active metabolite M8 by 89 and 92%, respectively. The manufacturers of omeprazole state that concomitant use with nelfinavir is not recommended.

Raltegravir

Concomitant use of omeprazole with raltegravir resulted in substantially increased peak plasma concentration and AUC of raltegravir; however, no dosage adjustment is recommended when proton-pump inhibitors are used concomitantly with raltegravir.

Rilpivirine

Concomitant use of omeprazole with rilpivirine resulted in decreased plasma concentrations and AUC of rilpivirine. Concomitant use of rilpivirine and proton-pump inhibitors is contraindicated.

Saquinavir

Concomitant use of omeprazole 40 mg once daily and saquinavir 1 g twice daily (with ritonavir 100 mg twice daily) increased peak serum concentrations and AUC of saquinavir by 75 and 82%, respectively. If omeprazole is used concomitantly with ritonavir-boosted saquinavir, clinical and laboratory monitoring for saquinavir toxicity is recommended, and reduction of saquinavir dosage should be considered.

Tipranavir

Concomitant use of omeprazole with ritonavir-boosted tipranavir resulted in decreased plasma concentrations of omeprazole; plasma concentrations of tipranavir were not affected. An increase in omeprazole dosage may be required when omeprazole is used concomitantly with ritonavir-boosted tipranavir.

Cilostazol

Concomitant use of omeprazole (40 mg daily for one week) and cilostazol in healthy individuals resulted in increased peak plasma concentrations and AUC of cilostazol (by 18 and 16%, respectively) and one of its active metabolites (by 29 and 69%, respectively). Therefore, reduction of cilostazol dosage (from 100 mg twice daily to 50 mg twice daily) should be considered during such concomitant use.

Clarithromycin

Concomitant administration of clarithromycin (500 mg 3 times daily) and omeprazole (40 mg daily) in healthy men resulted in increases of 30, 89, and 34% in the peak plasma concentration, AUC, and elimination half-life, respectively, of omeprazole. Increases in omeprazole AUC and half-life had a modest effect on gastric pH; mean 24-hour gastric pH was 5.2 when omeprazole was administered alone versus 5.7 with concomitant administration of clarithromycin. Acid suppression resulting from omeprazole appears to enhance the activity of anti-infective therapy against H. pylori. Serum concentrations and AUCs of clarithromycin and 14-hydroxyclarithromycin also are increased by concomitant administration of omeprazole.

Clopidogrel

Because omeprazole inhibits CYP2C19, concurrent use of omeprazole with clopidogrel, which is metabolized to its active metabolite by CYP2C19, reduces plasma concentrations of clopidogrel's active metabolite and potentially may reduce clopidogrel's clinical efficacy.

In a crossover clinical trial in healthy individuals who received clopidogrel (a 300-mg loading dose, followed by 75 mg daily) alone or with omeprazole (80 mg administered at the same time as the clopidogrel dose) for 5 days, exposure to the active metabolite of clopidogrel was decreased by 46% and 42% on days 1 and 5, respectively, when the drugs were administered simultaneously. In addition, mean inhibition of platelet aggregation was reduced by 47% at 24 hours and by 30% on day 5. When administration of the 2 drugs (at the same dosages) was separated by 12 hours in another study, results were similar. Concomitant use of clopidogrel and omeprazole also has been associated with decreased antiplatelet effects as determined by vasodilator-stimulated phosphoprotein (VASP) phosphorylation.

The clinical importance of these effects has not yet been established but reduction in clopidogrel's effectiveness in preventing cardiovascular events is possible. Several observational studies involving large numbers of patients suggest that proton-pump inhibitors reduce the effectiveness of clopidogrel in preventing cardiovascular events (e.g., recurrent myocardial infarction, rehospitalization for acute coronary syndromes, urgent target vessel revascularization, death). However, data discounting the clinical importance of an interaction between clopidogrel and proton-pump inhibitors also have been reported. Some experts, including the American College of Cardiology (ACC) and the American Heart Association (AHA), state that additional data from large, prospective trials are needed to fully elucidate the clinical consequences, if any, of the observed interaction between clopidogrel and certain proton-pump inhibitors, including omeprazole.

Proton-pump inhibitors vary in their potency for inhibiting CYP2C19. The change in inhibition of adenosine diphosphate (ADP)-induced platelet aggregation associated with concomitant use of proton-pump inhibitors with clopidogrel is related to the change in exposure to the active metabolite of clopidogrel. In pharmacokinetic and pharmacodynamic studies in healthy individuals, concomitant use of dexlansoprazole, lansoprazole, or pantoprazole had less effect on the antiplatelet activity of clopidogrel than did concomitant use of omeprazole or esomeprazole. For further information on interactions between proton-pump inhibitors and clopidogrel, Concomitant use of clopidogrel and either omeprazole or esomeprazole should be avoided. Administration of the drugs at separate times will not prevent the interaction.

The decision to use a proton-pump inhibitor concomitantly with clopidogrel should be based on the assessed risks and benefits in individual patients. The American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that the reduction in GI bleeding risk with proton-pump inhibitors is substantial in patients with risk factors for GI bleeding (e.g., advanced age; concomitant use of warfarin, corticosteroids, or nonsteroidal anti-inflammatory agents [NSAIAs]; H. pylori infection) and may outweigh any potential reduction in the cardiovascular efficacy of antiplatelet treatment associated with a drug-drug interaction. In contrast, ACCF/ACG/AHA states that patients without such risk factors receive little if any absolute risk reduction from proton-pump inhibitor therapy, and the risk/benefit balance may favor use of antiplatelet therapy without a proton-pump inhibitor in these patients.

If concomitant proton-pump inhibitor use is considered necessary, use of an agent with little or no CYP2C19-inhibitory activity should be considered. Alternatively, treatment with a histamine H2-receptor antagonist (ranitidine, famotidine, nizatidine) may be considered, although such agents may not be as effective as a proton-pump inhibitor in providing gastric protection; cimetidine should not be used since it also is a potent CYP2C19 inhibitor. There currently is no evidence that histamine H2-receptor antagonists (other than cimetidine) or other drugs that reduce gastric acid (e.g., antacids) interfere with the antiplatelet effects of clopidogrel.

Digoxin

Hypomagnesemia (e.g., resulting from long-term use of proton-pump inhibitors) sensitizes the myocardium to digoxin and, thus, may increase the risk of digoxin-induced cardiotoxic effects. In patients receiving digoxin, monitoring of magnesium concentrations should be considered prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.

Methotrexate

Data from case reports, population pharmacokinetic studies, and retrospective analyses suggest that concomitant use of proton-pump inhibitors, including omeprazole, with methotrexate may result in increased serum methotrexate concentrations and possibly result in toxicity. Increased serum concentrations and delayed clearance of methotrexate and/or its metabolite hydroxymethotrexate, with or without symptoms of methotrexate toxicity, have been reported in patients receiving methotrexate (usually at doses of 300 mg/m to 12 g/m) concomitantly with a proton-pump inhibitor. Although most of the reported cases occurred in patients receiving high doses of methotrexate, toxicity also has been reported in patients receiving low dosages of methotrexate (e.g., 15 mg per week) concomitantly with a proton-pump inhibitor. No formal studies of interactions between high-dose methotrexate and proton-pump inhibitors have been conducted to date.

The manufacturer of omeprazole states that temporary discontinuance of proton-pump inhibitor therapy may be considered in some patients receiving high-dose methotrexate therapy. Some clinicians recommend either withholding proton-pump inhibitor therapy for several days before and after methotrexate administration or substituting a histamine H2-receptor antagonist for the proton-pump inhibitor when acid suppressive therapy is indicated during methotrexate therapy. Pending further evaluation, some clinicians state that these recommendations should extend to patients receiving low-dose methotrexate.

Tacrolimus

Concomitant use of omeprazole with tacrolimus may result in increased serum concentrations of tacrolimus.

Voriconazole

Concomitant use of omeprazole (40 mg daily for 7 days) with voriconazole (a combined inhibitor of CYP2C19 and CYP3A4; 400 mg every 12 hours for one day, then 200 mg for 6 days) in healthy individuals increased peak plasma concentrations and AUC of omeprazole by an average of twofold and fourfold, respectively. Dosage adjustment of omeprazole usually is not required but may be considered in patients receiving high dosages (up to 240 mg daily), such as those with Zollinger-Ellison syndrome.

Warfarin

Increases in international normalized ratio (INR) and prothrombin time have been reported in patients receiving warfarin concomitantly with a proton-pump inhibitor, including omeprazole. Because such increases may lead to abnormal bleeding and death, monitoring of INR and prothrombin time may be necessary in patients receiving warfarin and a proton-pump inhibitor concomitantly.

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