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esomeprazole mag dr 40 mg cap (generic nexium)

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Uses

Gastroesophageal Reflux

Esomeprazole magnesium is used for short-term (4-8 weeks) treatment of diagnostically confirmed erosive esophagitis in patients with gastroesophageal reflux disease (GERD). The drug also is used as maintenance therapy following healing of erosive esophagitis to reduce recurrence of the disease. In addition, esomeprazole is used for short-term (4-8 weeks) treatment of symptoms (e.g., heartburn) of GERD in patients without erosive esophagitis. In infants, esomeprazole is used for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD. Potential benefits of proton-pump inhibitors in gastroesophageal reflux and esophagitis are thought to result principally from reduced acidity of gastric contents induced by the drugs and resultant reduced irritation of esophageal mucosa; the drugs can effectively relieve symptoms of esophagitis (e.g., heartburn) and promote healing of ulcerative and erosive lesions. Because esomeprazole (S-omeprazole) is not eliminated as rapidly as R-omeprazole, more drug reaches and blocks the proton pump, providing greater control of intragastric pH than racemic omeprazole.

Suppression of gastric acid secretion is considered by the American College of Gastroenterology (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. Because GERD is considered to be a chronic disease, the ACG states that many patients with GERD will require long-term, even lifelong, treatment. 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 for treatment of GERD, and are effective and appropriate as maintenance therapy in many patients with the disease. Proton-pump inhibitors also 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.

Efficacy of esomeprazole in the treatment of endoscopically diagnosed erosive esophagitis was established in 4 controlled studies in patients receiving esomeprazole 20 or 40 mg daily or omeprazole 20 mg daily for 8 weeks. Rates of healing and sustained resolution of heartburn achieved with esomeprazole were similar to or exceeded those achieved with omeprazole.

Efficacy in the long-term maintenance of healing was established in 2 controlled studies in patients with endoscopically confirmed healing of erosive esophagitis receiving esomeprazole 10, 20, or 40 mg daily or placebo for 6 months. Patients receiving esomeprazole remained in remission longer and experienced fewer recurrences than patients receiving placebo; although esomeprazole 10 mg daily provided less benefit than esomeprazole 20 or 40 mg daily, no additional benefit of the 40-mg daily dosage over the 20-mg daily dosage was reported.

Efficacy in patients with symptomatic GERD was established in 2 controlled studies in patients with a 6-month or longer history of heartburn episodes, no endoscopic evidence of erosive esophagitis, and heartburn for at least 4 of the 7 days immediately prior to randomization; patients received esomeprazole 20 or 40 mg daily or placebo for 4 weeks. The percentage of patients who were symptom-free was substantially higher in the group receiving esomeprazole than in the group receiving placebo; no additional benefit of the 40-mg dosage over the 20-mg dosage was reported.

In patients with erosive esophagitis who are unable to take esomeprazole orally, esomeprazole sodium may be used IV for short-term treatment of GERD. In several open-label crossover studies in patients with symptoms of GERD with or without erosive esophagitis, IV administration of esomeprazole 20 or 40 mg as either a 3-minute injection or a 15-minute infusion once daily for 10 days inhibited gastric acid secretion to a similar extent as the corresponding (20 or 40 mg) oral dosage of the drug.

For further information on the treatment of GERD,

Duodenal Ulcer

Esomeprazole magnesium is used in combination with amoxicillin and clarithromycin (triple therapy) for short-term (10 days) treatment of patients with H. pylori infection and duodenal ulcer disease (active duodenal ulcer or a history of duodenal ulcer within the preceding 5 years).

Efficacy of esomeprazole-based triple therapy for H. pylori eradication was established in 2 controlled studies in patients with documented H. pylori infection and at least one endoscopically verified duodenal ulcer (or documented history of duodenal ulcer disease in the preceding 5 years). At 4 weeks after treatment, H. pylori eradication rates were substantially higher in patients receiving triple therapy (esomeprazole 40 mg once daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily) for 10 days than in those receiving dual therapy (esomeprazole 40 mg daily and clarithromycin 500 mg twice daily) or monotherapy with esomeprazole 40 mg daily for 10 days.

Prevention of Nonsteroidal Anti-inflammatory Agent-induced Ulcers

Esomeprazole magnesium is used for reducing the occurrence of gastric ulcers associated with chronic nonsteroidal anti-inflammatory agent (NSAIA) therapy in patients at risk for developing these ulcers, including individuals 60 years of age or older and/or those with a documented history of gastric ulcers. Efficacy for this indication was established in two 6-month randomized, controlled studies in patients receiving chronic therapy with either a prototypical NSAIA or a selective cyclooxygenase-2 (COX-2) inhibitor; individuals enrolled in these studies were considered to be at risk for developing NSAIA-associated ulcers because of their age (60 years or older) and/or a history of documented gastric or duodenal ulcer within the previous 5 years, but they had no evidence of gastric or duodenal ulcers on endoscopic examination at the start of the studies. Results of the studies indicated that esomeprazole 20 or 40 mg daily was more effective than placebo in preventing gastric ulcer occurrence during 6 months of treatment; however, no additional benefit was observed with the 40-mg daily dosage compared with the 20-mg daily dosage. In these studies, 94.7-95.4% of patients receiving esomeprazole 20 mg daily, 95.3-96.7% of those receiving esomeprazole 40 mg daily, and 83.3-88.2% of those receiving placebo remained free of gastric ulcers, as determined by serial endoscopic examinations, throughout the 6-month study. The occurrence rate of duodenal ulcers was too low to determine the effect of esomeprazole therapy on duodenal ulcer occurrence.

In 2 other randomized studies, combined therapy with esomeprazole and naproxen was associated with a lower cumulative incidence of gastric ulcer compared with naproxen therapy alone over 6 months of treatment (4.1-7.1 versus 23.1-24.3%). Patients in these studies were randomized to receive either esomeprazole in fixed combination with naproxen (as immediate-release esomeprazole 20 mg and delayed-release naproxen 500 mg twice daily) or delayed-release naproxen (500 mg twice daily) alone. In both studies, patients receiving combined therapy with esomeprazole and naproxen were less likely than patients receiving naproxen alone to discontinue therapy because of adverse upper GI effects, including duodenal ulcers (4 versus 12%). Most patients (83%) in these studies were 50-69 years of age; those younger than 50 years of age were required to have a history of documented gastric or duodenal ulcer within the previous 5 years. About one-fourth of patients also received low-dose aspirin. Efficacy in patients receiving concomitant aspirin therapy was similar to that in the overall study population.

Pathologic GI Hypersecretory Conditions

Esomeprazole magnesium is used for the long-term treatment of pathologic GI hypersecretory conditions. Efficacy for this indication was established in an open-label study in a limited number of patients with previously diagnosed pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, idiopathic gastric acid hypersecretion); patients received total daily dosages of esomeprazole ranging from 80 mg-240 mg. The drug generally was well tolerated at these dosages for the duration of the study (12 months). At 12 months of therapy, 90% of patients treated with esomeprazole had controlled basal acid output (BAO) levels, defined as BAO of less than 5 or 10 mEq/hour in patients who had or had not previously undergone gastric acid-reducing surgery, respectively.

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. 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., H2-receptor antagonists, cytoprotective agents, antacids, and/or sucralfate).

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

Dosage and Administration

Administration

Oral Administration

Esomeprazole magnesium is administered orally once or twice daily. Because the area under the plasma concentration-time curve (AUC) of a single 40-mg dose of esomeprazole administered after the intake of food is decreased by 43-53%, the manufacturer states that esomeprazole magnesium delayed-release capsules and delayed-release oral suspension should be taken at least 1 hour before a meal. The manufacturer states that tablets containing immediate-release esomeprazole magnesium in fixed combination with delayed-release naproxen should taken at least 30 minutes before a meal.

Esomeprazole Oral Capsules

Esomeprazole magnesium delayed-release capsules should be swallowed whole and the contents should not be crushed or chewed. Alternatively, for patients with difficulty swallowing, the contents of a capsule may be mixed with a tablespoon of applesauce and swallowed immediately. The applesauce should not be hot and should be soft enough to be swallowed without chewing. The applesauce and esomeprazole enteric-coated granule mixture should not be stored for future use.

For patients with a nasogastric tube, the contents of a capsule can be mixed with 50 mL of water in a 60-mL catheter-tipped syringe. The syringe should be shaken vigorously for 15 seconds and then held with the tip pointed up and inspected for dissolved or disintegrated granules and granules remaining in the tip. The mixture should not be used if dissolved or disintegrated granules are observed. The mixture should be administered immediately and the tube should be flushed with additional water.

Esomeprazole Oral Suspension

For reconstitution of esomeprazole magnesium for delayed-release oral suspension in single-dose packets, the contents of a 2.5- or 5-mg packet should be mixed thoroughly with 5 mL of water and the contents of a 10-, 20-, or 40-mg packet should be mixed thoroughly with 15 mL of water; the mixture should be allowed to thicken for 2-3 minutes. If a single dose requires 2 packets, the oral suspension may be reconstituted with twice the amount of water needed for 1 packet. Within 30 minutes of preparation, the mixture should be stirred and consumed. If any material remains after the mixture is ingested, additional water should be added, mixed, and ingested immediately.

For patients with a nasogastric or gastric tube, the contents of a 2.5- or 5-mg packet should be mixed with 5 mL of water and the contents of a 10-, 20-, or 40-mg packet should be mixed with 15 mL of water 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.

Esomeprazole and Naproxen Fixed-combination Tablets

Tablets containing immediate-release esomeprazole magnesium in fixed combination with delayed-release naproxen should be swallowed whole with liquid, and should not be split, chewed, crushed, or dissolved.

IV Administration

Esomeprazole sodium is administered by IV injection over no less than 3 minutes or by IV infusion over 10-30 minutes.

For direct IV injection of a 20- or 40-mg dose in adults, esomeprazole sodium powder for injection is reconstituted by adding 5 mL of 0.9% sodium chloride injection to a vial labeled as containing 20 or 40 mg of esomeprazole. A volume of 5 mL of reconstituted solution (20 or 40 mg, respectively) should be withdrawn from the vial and injected over a period of no less than 3 minutes. Reconstituted solutions should be stored at room temperature (up to 30°C) and used within 12 hours of reconstitution. Each vial of esomeprazole sodium is intended for single use only.

For IV infusion of a 20- or 40-mg dose in adults, esomeprazole sodium powder for injection is reconstituted by adding 5 mL of 0.9% sodium chloride injection, lactated Ringer's injection, or 5% dextrose injection to a vial labeled as containing 20 or 40 mg of esomeprazole. The reconstituted solution should be further diluted with 0.9% sodium chloride injection, lactated Ringer's injection, or 5% dextrose injection to a final volume of 50 mL prior to IV infusion over 10-30 minutes. Esomeprazole sodium infusion solutions prepared using 0.9% sodium chloride injection or lactated Ringer's injection should be stored at room temperature (up to 30°C) and used within 12 hours of preparation; infusion solutions prepared using 5% dextrose injection should be stored at room temperature (up to 30°C) and used within 6 hours.

For IV infusion in pediatric patients 1 month to 17 years of age, esomeprazole sodium powder for injection is reconstituted by adding 5 mL of 0.9% sodium chloride injection to a vial labeled as containing 20 or 40 mg of esomeprazole to provide a solution containing 4 or 8 mg/mL, respectively. The reconstituted 4- or 8-mg/mL solution should be further diluted with 0.9% sodium chloride injection to a final volume of 50 mL to yield a final concentration of 0.4 or 0.8 mg/mL, respectively. The appropriate dose of esomeprazole should be withdrawn from the diluted solution and administered as an IV infusion over 10-30 minutes.

Parenteral esomeprazole sodium solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The manufacturer states that esomeprazole sodium should not be administered simultaneously through the same IV line with other drugs. The IV line should be flushed with 0.9% sodium chloride injection, lactated Ringer's injection, or 5% dextrose injection before and after esomeprazole administration.

Dosage

Dosage of esomeprazole magnesium or esomeprazole sodium is expressed in terms of esomeprazole.

Duration of therapy with a proton-pump inhibitor should be based on safety and efficacy data associated with a specific indication, dosing frequency as described by the manufacturer, and the needs of individual patients. The potential benefits versus possible risks of initiating or continuing proton-pump inhibitor therapy should be weighed carefully.

Adult Dosage

Gastroesophageal Reflux

The recommended oral dosage of esomeprazole for short-term treatment of erosive esophagitis in adults with GERD is 20 or 40 mg once daily for 4-8 weeks; an additional 4- to 8-week course of treatment may be considered if esophageal healing is incomplete after the first course of treatment. For maintenance therapy following healing of erosive esophagitis, the recommended adult oral dosage of esomeprazole is 20 mg once daily; the manufacturer states that controlled studies of esomeprazole maintenance therapy beyond 6 months have not been performed. The recommended oral dosage for the short-term treatment of symptomatic GERD in adults without erosive esophagitis is 20 mg once daily for 4 weeks; the manufacturer states that an additional 4-week course of therapy may be considered in patients whose symptoms have not completely resolved after the first course of treatment. 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.

In adults with erosive esophagitis who are unable to take esomeprazole orally, the usual dosage of IV esomeprazole for treatment of GERD is 20 or 40 mg administered by IV injection (over no less than 3 minutes) or by IV infusion (over 10-30 minutes) once daily; safety and efficacy of IV use beyond 10 days have not been established. Treatment with IV esomeprazole should be discontinued as soon as the patient is able to take the drug orally.

Duodenal Ulcer

When esomeprazole is used in combination with amoxicillin and clarithromycin (triple therapy) for eradication of H. pylori infection in patients with duodenal ulcer disease (active duodenal ulcer or a history of duodenal ulcer in the preceding 5 years), the recommended adult oral dosage is 40 mg once daily for 10 days.

Prevention of Nonsteroidal Anti-inflammatory Agent-induced Ulcers

For reducing the risk of nonsteroidal anti-inflammatory agent (NSAIA)-induced gastric ulcer, the usual adult oral dosage of esomeprazole is 20 or 40 mg once daily for up to 6 months; the manufacturer states that controlled studies of esomeprazole therapy in patients considered to be at risk for NSAIA-induced gastric ulcers did not extend beyond 6 months. When esomeprazole is administered in fixed combination with naproxen, the recommended adult dosage of esomeprazole is 20 mg (with naproxen 375 or 500 mg) twice daily. The fixed-combination preparation should not be used in patients requiring a total daily esomeprazole dosage of less than 40 mg.

Pathologic GI Hypersecretory Conditions

The recommended adult oral dosage of esomeprazole for the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome) is 40 mg twice daily. The manufacturer states that the dosage should be adjusted to individual patient needs; dosages up to 240 mg daily for up to 12 months have been administered.

Pediatric Dosage

Oral dosage of esomeprazole for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD in infants 1 month to less than 1 year of age is based on weight. Infants weighing 3-5 kg may receive an oral esomeprazole dosage of 2.5 mg once daily, those weighing more than 5 kg but not more than 7.5 kg may receive 5 mg once daily, and those weighing more than 7.5 kg but not more than 12 kg may receive 10 mg once daily. The manufacturer states that dosages exceeding 1.33 mg/kg daily have not been studied in infants 1 month to less than 1 year of age.

The recommended oral dosage for the short-term treatment of symptomatic GERD in children 1-11 years of age without erosive esophagitis is 10 mg once daily for up to 8 weeks. The recommended oral dosage of esomeprazole for the short-term treatment of erosive esophagitis in children 1-11 years of age weighing less than 20 kg is 10 mg once daily for 8 weeks; 10 or 20 mg once daily for 8 weeks is recommended in children 1-11 years of age weighing 20 kg or more. The manufacturer states that dosages exceeding 1 mg/kg daily have not been studied in children 1-11 years of age.

The recommended oral dosage of esomeprazole for the short-term treatment of GERD in adolescents 12-17 years of age is 20 or 40 mg once daily for up to 8 weeks.

Pediatric patients who are unable to take esomeprazole orally for the treatment of GERD with erosive esophagitis may receive the drug IV. Infants 1 month to less than 1 year of age may receive an IV esomeprazole dosage of 0.5 mg/kg once daily; children and adolescents 1- 17 years of age may receive an IV dosage of 10 mg once daily if they weigh less than 55 kg or 20 mg once daily in they weigh 55 kg or more. Esomeprazole should be administered by IV infusion (over 10-30 minutes) in infants, children, and adolescents. Treatment with IV esomeprazole should be discontinued as soon as the patient is able to take the drug orally.

Special Populations

The oral or IV dosage of esomeprazole in patients with severe hepatic impairment (Child-Pugh class C) should not exceed 20 mg daily because AUCs of esomeprazole in such patients are 2-3 times greater than those in patients with normal hepatic function. Dosage adjustment is not necessary in patients with mild to moderate (Child-Pugh class A or B) hepatic impairment, patients with renal impairment, or geriatric patients. However, the commercially available tablets containing esomeprazole magnesium in fixed combination with naproxen are not recommended for use in patients with severe hepatic impairment or moderate to severe renal impairment (creatinine clearance less than 30 mL/minute).

Cautions

Contraindications

Known hypersensitivity to esomeprazole or other substituted benzimidazoles (e.g., lansoprazole, omeprazole, pantoprazole, rabeprazole) or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, anaphylactic shock) have been reported with esomeprazole.

Gastric Malignancy

Symptomatic response to therapy with esomeprazole does not preclude the presence of gastric malignancy.

Atrophic Gastritis

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

Clostridium difficile Infection

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.

Musculoskeletal Effects

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 risk is unclear; causality has not been established. FDA is continuing to evaluate this safety concern. 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 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.

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 esomeprazole. 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. 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 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.(See Cautions: Hypomagnesemia and also

Interactions with Diagnostic Tests for Neuroendocrine Tumors

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 esomeprazole therapy before assessing CgA concentrations and consider repeating the test if initial CgA concentrations are high.

Cardiac Effects

Although preliminary safety data from 2 long-term clinical trials comparing esomeprazole or omeprazole 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, the US Food and Drug Administration (FDA) has reviewed safety data from these and other studies of the drugs and has concluded that long-term use of esomeprazole or omeprazole 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.

Respiratory Effects

Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia). (For further precautionary information about this adverse effect, .)

Use of Fixed Combinations

When esomeprazole is used in fixed combination with naproxen, the usual cautions, precautions, and contraindications associated with naproxen must be considered in addition to those associated with esomeprazole.

Specific Populations

Pregnancy

Category B.

Lactation

It is unknown whether esomeprazole is distributed into milk. However, omeprazole is distributed into human milk; discontinue nursing or drug because of potential risk in nursing infants.

Pediatric Use

Safety and efficacy of oral esomeprazole for short-term (4-8 weeks) treatment of GERD in pediatric patients 1-17 years of age are supported by evidence from controlled clinical trials in adults and by safety and pharmacokinetic studies in children and adolescents. Safety and tolerability of oral esomeprazole 5, 10, or 20 mg daily for up to 8 weeks were evaluated in children 1-11 years of age with endoscopically diagnosed GERD; the presence or absence of erosive esophagitis was confirmed endoscopically in this study. Safety and tolerability of oral esomeprazole 20 or 40 mg daily for up to 8 weeks were evaluated in adolescents 12-17 years of age with clinically diagnosed GERD; the presence or absence of erosive esophagitis was not confirmed endoscopically in this study. Adverse effects reported in children and adolescents were similar to those reported during clinical trials in adults; however, a higher incidence of somnolence was reported in children.

Safety and efficacy of oral esomeprazole for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD in infants 1 month to less than 1 year of age are supported by controlled clinical trials in adults and by safety, pharmacokinetic, and pharmacodynamic studies in pediatric patients. The most commonly reported adverse effects in infants 1-11 months of age receiving oral esomeprazole include irritability and vomiting.

Safety and efficacy of oral esomeprazole for other uses in pediatric patients have not been established. In a randomized, controlled, treatment-withdrawal study in infants 1-11 months of age with symptomatic GERD (diagnosed clinically in most patients), the proportion of patients discontinuing treatment because of worsening symptoms was similar in the esomeprazole and placebo groups.

Safety and efficacy of IV esomeprazole for short-term treatment of GERD with erosive esophagitis in pediatric patients 1 month to 17 years of age are supported by pharmacokinetic studies of IV esomeprazole in pediatric patients and adults and by pharmacodynamic studies of oral esomeprazole in pediatric patients and of IV esomeprazole in adults. Adverse effects of IV esomeprazole in pediatric patients 1 month to 17 years of age were consistent with the known safety profile of the drug.

Safety and efficacy of IV esomeprazole in neonates younger than 1 month of age have not been established.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity of some older patients cannot be ruled out.

Severe Hepatic Impairment

Use with caution.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 1% or more of patients receiving oral esomeprazole include headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. Common adverse effects of IV esomeprazole generally are similar to those reported with oral esomeprazole, although injection site reaction, dizziness/vertigo, and pruritus also occur commonly with IV administration.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Esomeprazole is extensively metabolized by the cytochrome P-450 (CYP) 2C19 isoenzyme and to a lesser extent by CYP3A4. Esomeprazole also may interfere with CYP2C19 activity.

Potential pharmacokinetic interaction with drugs metabolized by CYP2C19 (esomeprazole-induced inhibition of metabolism). Concomitant administration of esomeprazole and diazepam (a CYP2C19 substrate) decreased diazepam clearance by 45%.

Concomitant use of esomeprazole and cilostazol, a substrate of CYP3A4 and CYP2C19, is expected to result in increased concentrations of cilostazol and its active metabolite; therefore, reduction of cilostazol dosage (from 100 mg twice daily to 50 mg twice daily) should be considered during such concomitant use.

Pharmacokinetic interaction with drugs metabolized by CYP isoenzymes 3A4, 1A2, 2A6, 2C9, 2D6, or 2E1 is considered unlikely.

Potential pharmacokinetic interaction (esomeprazole exposure may increase more than twofold) with combined inhibitors of CYP2C19 and CYP3A4 (e.g., voriconazole); dosage adjustment of esomeprazole 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.

Potential pharmacokinetic interaction (decreased esomeprazole concentrations) with drugs that induce CYP2C19 and/or CYP3A4 (e.g., St. John's wort [Hypericum perforatum], rifampin). Concomitant use of omeprazole, of which esomeprazole is an enantiomer, and St. John's wort (300 mg 3 times daily for 14 days) in healthy men resulted in decreased systemic exposure to omeprazole; peak plasma concentrations and area under the plasma 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 esomeprazole with St. John's wort or rifampin should be avoided.

Drugs that Cause Hypomagnesemia

Potential pharmacologic interaction (possible increased risk of 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 Hypomagnesemia under Cautions: Warnings/Precautions.)

Gastric pH-dependent Drugs

Potential pharmacokinetic interaction (altered absorption at increased gastric pH) with gastric pH-dependent drugs (e.g., ketoconazole, iron salts, digoxin, atazanavir, erlotinib).

Concomitant use of omeprazole 20 mg once daily and digoxin in healthy individuals increased digoxin bioavailability by 10% (up to 30% in some individuals). Because esomeprazole is an enantiomer of omeprazole, concomitant use of esomeprazole with digoxin is expected to increase systemic exposure to digoxin; therefore, monitoring for manifestations of digoxin toxicity may be required during such concomitant use.

Absorption of ketoconazole, iron salts, atazanavir, or erlotinib may be decreased in patients receiving esomeprazole concomitantly.

Antiretroviral Agents

Atazanavir

Potential pharmacokinetic interaction (possible altered oral absorption of atazanavir at increased gastric pH, resulting in decreased plasma atazanavir concentrations). 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 or development of drug resistance. Concomitant use of omeprazole 40 mg once daily (administered 2 hours before atazanavir) and atazanavir 400 mg once daily decreased the AUC and peak plasma concentration of atazanavir by 94 and 96%, respectively. The manufacturer of esomeprazole states that concomitant administration 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.

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

Potential pharmacokinetic interaction (decreased plasma nelfinavir concentrations). 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 manufacturer of esomeprazole states that concomitant administration with nelfinavir is not recommended.

Raltegravir

Pharmacokinetic interaction with omeprazole (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

Pharmacokinetic interaction with omeprazole (decreased plasma concentrations and AUC of rilpivirine). Concomitant use of other proton-pump inhibitors also may result in decreased plasma concentration of rilpivirine. Concomitant use of rilpivirine and proton-pump inhibitors is contraindicated.

Saquinavir

Potential pharmacokinetic interaction (increased peak plasma concentration and AUC of saquinavir). Concomitant use of omeprazole 40 mg once daily and ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily) increased the peak plasma concentration and AUC of saquinavir by 75 and 82%, respectively. Caution is advised if proton-pump inhibitors are used concomitantly with ritonavir-boosted saquinavir, and patients should be monitored for saquinavir toxicity. The manufacturer of esomeprazole states that dosage reduction of saquinavir may be considered on an individual basis.

Clopidogrel

Potential pharmacokinetic interaction (decreased plasma concentration of the active metabolite of clopidogrel) and pharmacodynamic interaction (reduced antiplatelet effects) between proton-pump inhibitors and clopidogrel. Clopidogrel is metabolized to its active metabolite by CYP2C19. Concurrent use of omeprazole or esomeprazole, which inhibit CYP2C19, with clopidogrel reduces exposure to the active metabolite of clopidogrel and decreases platelet inhibitory effects. Although the clinical importance has not been fully elucidated, a reduction in the effectiveness of clopidogrel in preventing cardiovascular events is possible. 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 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. In individuals who were extensive metabolizers of CYP2C19 substrates, use of esomeprazole (40 mg once daily) concomitantly with clopidogrel (75 mg once daily) for 9 days reduced exposure to the active metabolite of clopidogrel by about 16% compared with use of clopidogrel alone. The manufacturer of clopidogrel states that concomitant use of esomeprazole and clopidogrel should be avoided.

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 therapy with a proton-pump inhibitor and clopidogrel 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. For further information on interactions between proton-pump inhibitors and 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

Potential pharmacokinetic interaction (increased serum methotrexate concentrations, possibly resulting in toxicity) when proton-pump inhibitors, including esomeprazole, are used concomitantly with methotrexate. 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 esomeprazole 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.

Nonsteroidal Anti-inflammatory Agents

Pharmacokinetic interactions with naproxen or rofecoxib (no longer commercially available in the US) are unlikely.

Sucralfate

In a single-dose study, concomitant administration of omeprazole 20 mg and sucralfate 1 g resulted in delayed absorption of omeprazole and decreased omeprazole bioavailability by 16%. Proton-pump inhibitors should be administered at least 30 minutes before sucralfate.

Tacrolimus

Potential pharmacokinetic interaction (increased serum concentrations of tacrolimus).

Warfarin

Potential increased international normalized ratio (INR) and prothrombin time when warfarin is used concomitantly with proton-pump inhibitors, including esomeprazole. Potential for abnormal bleeding and death; monitor for INR and prothrombin time increases when esomeprazole is used concomitantly with warfarin.

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