NEXIUM

REMEDYREPACK INC.

These highlights do not include all the information needed to use NEXIUM safely and effectively. See full prescribing information for NEXIUM.NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, for Oral Use NEXIUM (esomeprazole magnesium) For Delayed-Release Oral SuspensionInitial U.S. Approval: 1989 (omeprazole)

FULL PRESCRIBING INFORMATION: CONTENTS*

• RECENT MAJOR CHANGES
• INDICATIONS & USAGE
• DOSAGE & ADMINISTRATION
• DOSAGE FORMS & STRENGTHS
• NEXIUM CONTRAINDICATIONS
• WARNINGS AND PRECAUTIONS
• NEXIUM ADVERSE REACTIONS
• DRUG INTERACTIONS
• USE IN SPECIFIC POPULATIONS
• OVERDOSAGE
• NEXIUM DESCRIPTION
• CLINICAL PHARMACOLOGY
• NONCLINICAL TOXICOLOGY
• CLINICAL STUDIES
• HOW SUPPLIED
• INFORMATION FOR PATIENTS
• SPL MEDGUIDE
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

FULL PRESCRIBING INFORMATION

INDICATIONS & USAGE

Healing of Erosive Esophagitis

NEXIUM is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed erosive esophagitis. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4 to 8 week course of NEXIUM may be considered.

In infants 1 month to less than 1 year, NEXIUM is indicated for short-term treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD.

Maintenance of Healing of Erosive Esophagitis

NEXIUM is indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled studies do not extend beyond 6 months.

Symptomatic Gastroesophageal Reflux Disease

NEXIUM is indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults and children 1 year or older.

Triple Therapy (NEXIUM plus amoxicillin and clarithromycin): NEXIUM, in combination with amoxicillin and clarithromycin, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Dosage and Administration (2) and Clinical Studies (14) ].

In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see Clinical Pharmacology (12.4) and the prescribing information for clarithromycin].

DOSAGE & ADMINISTRATION

NEXIUM is supplied as delayed-release capsules for oral administration or in packets for preparation of delayed-release oral suspensions. The recommended dosages are outlined in Table 1. NEXIUM should be taken at least one hour before meals.

The duration of proton pump inhibitor administration should be based on available safety and efficacy data specific to the defined indication and dosing frequency, as described in the prescribing information, and individual patient medical needs. Proton pump inhibitor treatment should only be initiated and continued if the benefits outweigh the risks of treatment.

Please refer to amoxicillin and clarithromycin prescribing information for Contraindications, Warnings, and dosing in elderly and renally-impaired patients.

Special Populations

Hepatic Insufficiency

In patients with mild to moderate liver impairment (Child Pugh Classes A and B), no dosage adjustment is necessary. For patients with severe liver impairment (Child Pugh Class C), a dose of 20 mg of NEXIUM should not be exceeded [see Clinical Pharmacology (12.3) ].

Directions for use specific to the route and available methods of administration for each of these dosage forms are presented in Table 2.

Table 2: Administration Options

NEXIUM Delayed-Release Capsules

NEXIUM Delayed-Release Capsules should be swallowed whole.

Alternatively, for patients who have difficulty swallowing capsules, one tablespoon of applesauce can be added to an empty bowl and the NEXIUM Delayed-Release Capsule can be opened, and the granules inside the capsule carefully emptied onto the applesauce. The granules should be mixed with the applesauce and then swallowed immediately: do not store for future use. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The granules should not be chewed or crushed. If the granules/applesauce mixture is not used in its entirety, the remaining mixture should be discarded immediately.

For patients who have a nasogastric tube in place, NEXIUM Delayed-Release Capsules can be opened and the intact granules emptied into a 60 mL catheter tipped syringe and mixed with 50 mL of water. It is important to only use a catheter tipped syringe when administering NEXIUM through a nasogastric tube. Replace the plunger and shake the syringe vigorously for 15 seconds. Hold the syringe with the tip up and check for granules remaining in the tip. Attach the syringe to a nasogastric tube and deliver the contents of the syringe through the nasogastric tube into the stomach. After administering the granules, the nasogastric tube should be flushed with additional water. Do not administer the granules if they have dissolved or disintegrated.

The mixture must be used immediately after preparation.

NEXIUM For Delayed-Release Oral Suspension

NEXIUM For Delayed-Release Oral Suspension should be administered as follows:

For patients who have a nasogastric or gastric tube in place, NEXIUM For Delayed-Release Oral Suspension can be administered as follows:

DOSAGE FORMS & STRENGTHS

NEXIUM Delayed-Release Capsules, 20 mg - opaque, hard gelatin, amethyst colored capsules with two radial bars in yellow on the cap and NEXIUM 20 mg in yellow on the body.

NEXIUM Delayed-Release Capsules, 40 mg - opaque, hard gelatin, amethyst colored capsules with three radial bars in yellow on the cap and NEXIUM 40 mg in yellow on the body.

NEXIUM For Delayed-Release Oral Suspension, 2.5 mg, 5 mg, 10 mg, 20 mg or 40 mg - unit dose packet containing a fine yellow powder, consisting of white to pale brownish esomeprazole granules and pale yellow inactive granules.

NEXIUM CONTRAINDICATIONS

NEXIUM is contraindicated in patients with known hypersensitivity to proton pump inhibitors. Hypersensitivity reactions, e.g., angioedema and anaphylactic shock, have been reported with NEXIUM use.

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with NEXIUM, refer to the CONTRAINDICATIONS section of their package inserts.

WARNINGS AND PRECAUTIONS

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

Published observational studies suggest that PPI therapy like NEXIUM may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Clostridium diffficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with NEXIUM, refer to WARNINGS and PRECAUTIONS sections of those package inserts.

Avoid concomitant use of NEXIUM with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using NEXIUM consider alternative anti-platelet therapy. [see Drug Interactions (7.3) and Pharmacokinetics (12.3) ]

Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. [see Dosage and Administration (2) and Adverse Reactions (6.2) ]

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See Adverse Reactions (6.2) ]

Drugs which induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampin) can substantially decrease esomeprazole concentrations. [see Drug Interactions (7.3) ] Avoid concomitant use of NEXIUM with St John’s Wort, or rifampin.

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients. [see Drug Interactions (7.7) ]

NEXIUM ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

The safety of NEXIUM was evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6-12 months. In general, NEXIUM was well tolerated in both short and long-term clinical trials.

The safety in the treatment of healing of erosive esophagitis was assessed in four randomized comparative clinical trials, which included 1,240 patients on NEXIUM 20 mg, 2,434 patients on NEXIUM 40 mg, and 3,008 patients on omeprazole 20 mg daily. The most frequently occurring adverse reactions (≥1%) in all three groups were headache (5.5, 5, and 3.8, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking NEXIUM or omeprazole.

Additional adverse reactions that were reported as possibly or probably related to NEXIUM with an incidence < 1% are listed below by body system:

Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors;

Cardiovascular: flushing, hypertension, tachycardia;

Endocrine: goiter;

Gastrointestinal: bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting;

Hearing: earache, tinnitus;

Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia;

Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased;

Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease;

Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica;

Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect;

Reproductive: dysmenorrhea, menstrual disorder, vaginitis;

Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis;

Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria;

Special Senses: otitis media, parosmia, taste loss, taste perversion;

Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria;

Visual: conjunctivitis, vision abnormal.

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to NEXIUM, were reported in ≤ 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone [see Clinical Pharmacology (12) ]. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration.

The incidence of treatment-related adverse reactions during 6-month maintenance treatment was similar to placebo. There were no differences in types of related adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment.

Two placebo-controlled studies were conducted in 710 patients for the treatment of symptomatic gastroesophageal reflux disease. The most common adverse reactions that were reported as possibly or probably related to NEXIUM were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%).

Pediatrics

The safety of NEXIUM was evaluated in 316 pediatric and adolescent patients aged 1 to 17 years in four clinical trials for the treatment of symptomatic GERD [see Clinical Studies (14.2) ]. In 109 pediatric patients aged 1 to 11 years, the most frequently reported (at least 1%) treatment-related adverse reactions in these patients were diarrhea (2.8%), headache (1.9%) and somnolence (1.9%). In 149 pediatric patients aged 12 to 17 years the most frequently reported (at least 2%) treatment-related adverse reactions in these patients were headache (8.1%), abdominal pain (2.7%), diarrhea (2%), and nausea (2%).

The safety of NEXIUM was evaluated in 167 pediatric patients from birth to <1 year of age in three clinical trials. [See Clinical Studies (14.3) ] In a study that included 26 pediatric patients aged birth to 1 month there were no treatment related adverse reactions. In a study that included 43 pediatric patients age 1 to 11 months, inclusive the most frequently reported (at least 5%) adverse reactions, irrespective of causality, were irritability and vomiting. In a study that included 98 pediatric patients, age 1 to 11 months, inclusive exposed to esomeprazole for up to 6 weeks (including 39 patients randomized to the withdrawal phase), there were 4 treatment-related adverse reactions: abdominal pain (1%), regurgitation (1%), tachypnea (1%), and increased ALT (1%).

No new safety concerns were identified in pediatric patients.

Combination Treatment with Amoxicillin and Clarithromycin

In clinical trials using combination therapy with NEXIUM plus amoxicillin and clarithromycin, no additional adverse reactions specific to these drug combinations were observed. Adverse reactions that occurred were limited to those observed when using NEXIUM, amoxicillin, or clarithromycin alone.

The most frequently reported drug-related adverse reactions for patients who received triple therapy for 10 days were diarrhea (9.2%), taste perversion (6.6%), and abdominal pain (3.7%). No treatment-emergent adverse reactions were observed at higher rates with triple therapy than were observed with NEXIUM alone.

For more information on adverse reactions with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions sections.

In clinical trials using combination therapy with NEXIUM plus amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed.

For more information on laboratory changes with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions section.

DRUG INTERACTIONS

Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction.

Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19.

Reduced concentrations of atazanavir and nelfinavir

For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C_max by 37% and 89% and C_min by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, C_max by 96%, and C_min by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.

Increased concentrations of saquinavir

For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in C_max by 75%, and in C_min by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with NEXIUM. Dose reduction of saquinavir should be considered from the safety perspective for individual patients.

There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of NEXIUM with clopidogrel. When using NEXIUM, consider use of alternative anti-platelet therapy [see Pharmaokinetics (12.3)].

Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_max and AUC of cilostazol by 18% and 26% respectively. C_max and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered.

Concomitant administration of esomeprazole and a combined inhibitor of CYP 2C19 and CYP 3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. However, in patients with Zollinger-Ellison’s Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered.

Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. John’s wort an inducer of CYP3A4. In a cross-over study in 12 healthy male subjects, St John’s wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (C_max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (C_max and AUC decreased by 49.6 % and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with NEXIUM.

Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors. [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2) ]

Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin [see Clinical Pharmacology (12.4) ].

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [see Contraindications in prescribing information for clarithromycin].

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.8) ].

USE IN SPECIFIC POPULATIONS

Pregnancy Category B

Reproductive studies in rats and rabbits with NEXIUM (esomeprazole) and multiple cohort studies in pregnant women with omeprazole use during the first trimester do not show an increased risk of congenital anomalies or adverse pregnancy outcomes. There are, however, no adequate and well controlled studies of NEXIUM use in pregnancy. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Esomeprazole is the s-isomer of omeprazole. In four population-based cohort studies that included 1226 women exposed during the first trimester of pregnancy to omeprazole there was no increased risk of congenital anomalies.

Reproductive studies with esomeprazole have been performed in rats at doses up to 57 times the human dose and in rabbits at doses up to 35 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus. [See Animal Toxicology and/or Pharmacology (13.2) ]

Reproductive studies conducted with omeprazole on rats at oral doses up to 56 times the human dose and in rabbits at doses up to 56 times the human dose did not show any evidence of teratogenicity. In pregnant rabbits, omeprazole at doses about 5.5 to 56 times the human dose produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy loss. In rats treated with omeprazole at doses about 5.6 to 56 times the human dose, dose-related embryo/fetal toxicity and postnatal developmental toxicity occurred in offspring.

Use of NEXIUM in pediatric and adolescent patients 1 to 17 years of age for short-term treatment (up to eight weeks) of GERD is supported by extrapolation of results from adequate and well-controlled studies for adults and safety and pharmacokinetic studies performed in pediatric and adolescent patients [see Clinical Pharmacology (12.3), Dosage and Administration (2), Adverse Reactions (6.1), and Clinical Studies (14.3) ]. The safety and effectiveness of NEXIUM for other pediatric uses have not been established.

Erosive esophagitis due to acid-mediated GERD in infants 1 month to less than one year of age

Use of NEXIUM in pediatric patients 1 month to less than 1 year of age for treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD is supported by extrapolation of results from adequate and well-controlled studies for adults and safety, pharmacokinetic, and pharmacodynamic studies performed in pediatric patients [see Clinical Pharmacology (12.3), Dosage and Administration (2), Adverse Reactions (6.1), and Clinical Studies, (14.3) ].

Symptomatic GERD in infants 1 month to less than one year of age

There was no statistically significant difference between NEXIUM and placebo in the rate of discontinuation due to symptom worsening in a multicenter, randomized, double-blind, controlled, treatment-withdrawal study of 98 patients ages 1 to 11 months, inclusive. Patients were enrolled if they had either a clinical diagnosis of suspected GERD, symptomatic GERD, or endoscopically proven GERD. Twenty of 98 enrolled patients underwent endoscopy, and 6 patients were found to have erosive esophagitis on endoscopy at baseline. All patients received NEXIUM Delayed-Release Oral Suspension once daily during a two-week, open-label phase of the study.

There were 80 patients who attained a pre-specified level of symptom improvement and who entered the double-blind phase, in which they were randomized in equal proportions to receive NEXIUM or placebo for the next four weeks. Efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the four-week, treatment-withdrawal phase.

The following pharmacokinetic and pharmacodynamic information was obtained in pediatric patients with GERD aged birth to less than one year of age. In infants (1 to 11 months old, inclusive) given NEXIUM 1 mg/kg once daily, the percent time with intragastric pH > 4 increased from 29% at baseline to 69% on Day 7, which is similar to the pharmacodynamic effect in adults [see Clinical Pharmacology (12.2) ]. Apparent clearance (CL/F) increases with age in pediatric patients from birth to 2 years of age.

Neonates 0 to 1 month of age

Following administration of oral NEXIUM in neonates the geometric mean (range) for the apparent clearance (CL/F) was 0.55 L/h/kg (0.25-1.6 L/h/kg).

The safety and effectiveness of NEXIUM in neonates have not been established.

OVERDOSAGE

A single oral dose of esomeprazole at 510 mg/kg (about 103 times the human dose on a body surface area basis), was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions.

The symptoms described in connection with deliberate NEXIUM overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg of esomeprazole were uneventful. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert - Adverse Reactions ). No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive.

As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose contact a Poison Control Center at 1–800–222–1222.

NEXIUM DESCRIPTION

The active ingredient in the proton pump inhibitor NEXIUM^® (esomeprazole magnesium) Delayed-Release Capsules for oral administration and NEXIUM (esomeprazole magnesium) For Delayed-Release Oral Suspension is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. (Initial U.S. approval of esomeprazole magnesium: 2001). Its molecular formula is (C₁₇H₁₈N₃O₃S)₂Mg x 3 H₂O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. The structural formula is:

Figure 1

The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.

NEXIUM is supplied in delayed-release capsules and in packets for a delayed-release oral suspension. Each delayed-release capsule contains 20 mg, or 40 mg of esomeprazole (present as 22.3 mg, or 44.5 mg esomeprazole magnesium trihydrate) in the form of enteric-coated granules with the following inactive ingredients: glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate. The capsule shells have the following inactive ingredients: gelatin, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.

Each packet of NEXIUM For Delayed-Release Oral Suspension contains 2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg of esomeprazole, in the form of the same enteric-coated granules used in NEXIUM Delayed-Release Capsules, and also inactive granules. The inactive granules are composed of the following ingredients: dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose. The esomeprazole granules and inactive granules are constituted with water to form a suspension and are given by oral, nasogastric, or gastric administration.

 

 

CLINICAL PHARMACOLOGY

Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H⁺/K⁺-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.

In 24-month carcinogenicity studies of omeprazole in rats, a dose-related significant occurrence of gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Nonclinical Toxicology (13.1) ]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H₂-receptor antagonists.

Human gastric biopsy specimens have been obtained from more than 3,000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.

In over 1,000 patients treated with NEXIUM (10, 20 or 40 mg/day) up to 6 to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.

Endocrine Effects

NEXIUM had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of NEXIUM on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin.

The steady state pharmacokinetics of esomeprazole obtained after administration of 40 mg once daily to 4 patients each with mild (Child Pugh A), moderate (Child Pugh Class B), and severe (Child Pugh Class C) liver insufficiency were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic insufficiency, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic insufficiency the AUCs were 2 to 3 times higher than in the patients with normal liver function. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child Pugh Class C) a dose of 20 mg once daily should not be exceeded [see Dosage and Administration (2) ].

Renal Insufficiency

The pharmacokinetics of NEXIUM in patients with renal impairment are not expected to be altered relative to healthy volunteers as less than 1% of esomeprazole is excreted unchanged in urine.

Other pharmacokinetic observations

Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole.

Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of esomeprazole or these NSAIDs.

NEXIUM, amoxicillin, and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections [see Indications and Usage (1) and Clinical Studies (14)].

Helicobacter pylori: Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined.

Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥ 1 mcg/mL) to H. pylori was 15% (66/445) at baseline in all treatment groups combined. A total of > 99% (394/395) of patients had H. pylori isolates that were considered to be susceptible (MIC ≤ 0.25 mcg/mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5 mcg/mL.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are shown in the Table 8:

Patients not eradicated of H. pylori following NEXIUM/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori should not be re-treated with a clarithromycin-containing regimen.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes:

In the NEXIUM/amoxicillin/clarithromycin clinical trials, 83% (176/212) of the patients in the NEXIUM/amoxicillin/clarithromycin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori, and 17% (36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori on triple therapy, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori on triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin.

Susceptibility Test for Helicobacter pylori: For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

Effects on Gastrointestinal Microbial Ecology: Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.

Geometric mean;arithmetic meanDuration of treatment for 12 to 17 year olds and adults were 8 days and 5 days, respectively. Data were obtained from two independent studies.Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test resultsSusceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC ≥ 1.0 mcg/mL

 

NONCLINICAL TOXICOLOGY

The carcinogenic potential of NEXIUM was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44, and 141 mg/kg/day (about 0.7 to 57 times the human dose of 20 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 5.6 times the human dose on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for 2 years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive.

Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

 

Reproductive Toxicology Studies

Reproductive studies have been performed in rats at oral doses up to 280 mg/kg/day (about 57 times the human dose on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times the human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole.

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 56 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 56 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 5.5 to 56 times the human dose on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 5.6 to 56 times the human dose on a body surface area basis).

 

 

CLINICAL STUDIES

The healing rates of NEXIUM 40 mg, NEXIUM 20 mg, and omeprazole 20 mg (the approved dose for this indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in the Table 9:

Table 9: Erosive Esophagitis Healing Rate (Life-Table Analysis)

Study	No. of Patients	Treatment Groups	Week 4	Week 8	Significance Level *
1	588	NEXIUM 20 mg	68.7%	90.6%	N.S.†
	588	Omeprazole 20 mg	69.5%	88.3%
2	654	NEXIUM 40 mg	75.9%	94.1%	p < 0.001
	656	NEXIUM 20 mg	70.5%	89.9%	p < 0.05
	650	Omeprazole 20 mg	64.7%	86.9%
3	576	NEXIUM 40 mg	71.5%	92.2%	N.S.N.S. = not significant (p > 0.05)
	572	Omeprazole 20 mg	68.6%	89.8%
4	1216	NEXIUM 40 mg	81.7%	93.7%	p < 0.001
	1209	Omeprazole 20 mg	68.7%	84.2%

In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in the Table 10:

Table 10: Sustained Resolution* of Heartburn (Erosive Esophagitis Patients)

			Cumulative Percent† with Sustained Resolution
Study	No. of Patients	Treatment Groups	Day 14	Day 28	Significance Level ‡
1	573	NEXIUM 20 mg	64.3%	72.7%	N.S.§
	555	Omeprazole 20 mg	64.1%	70.9%
2	621	NEXIUM 40 mg	64.8%	74.2%	p <0.001
	620	NEXIUM 20 mg	62.9%	70.1%	N.S.N.S. = not significant (p > 0.05)
	626	Omeprazole 20 mg	56.5%	66.6%
3	568	NEXIUM 40 mg	65.4%	73.9%	N.S.N.S. = not significant (p > 0.05)
	551	Omeprazole 20 mg	65.5%	73.1%
4	1187	NEXIUM 40 mg	67.6%	75.1%	p <0.001
	1188	Omeprazole 20 mg	62.5%	70.8%

In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for NEXIUM 40 mg, 7 to 8 days for NEXIUM 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of NEXIUM with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of erosive esophagitis.

Long-Term Maintenance of Healing of Erosive Esophagitis

Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed erosive esophagitis to evaluate NEXIUM 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.

The percentages of patients that maintained healing of erosive esophagitis at the various time points are shown in the Figures 2 and 3:

Figure 2: Maintenance of Healing Rates by Month (Study 177)

s= scheduled visit

Figure 3: Maintenance of Healing Rates by Month (Study 178)

s= scheduled visit

Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with NEXIUM compared to placebo.

In both studies, the proportion of patients on NEXIUM who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo.

In a third multicenter open label study of 808 patients treated for 12 months with NEXIUM 40 mg, the percentage of patients that maintained healing of erosive esophagitis was 93.7% for six months and 89.4% for one year.

 

Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 patients comparing four weeks of treatment with NEXIUM 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms. Patients had ≥ 6-month history of heartburn episodes, no erosive esophagitis by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization.

The percentage of patients that were symptom-free of heartburn was significantly higher in the NEXIUM groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).

No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.

The percent of patients symptom-free of heartburn by day are shown in the Figures 4 and 5:

Figure 4: Percent of Patients Symptom-Free of Heartburn by Day (Study 225)

Figure 5: Percent of Patients Symptom-Free of Heartburn by Day (Study 226)

In three European symptomatic GERD trials, NEXIUM 20 mg and 40 mg and omeprazole 20 mg were evaluated. No significant treatment related differences were seen.

 

1 to 11 Years of Age

In a multicenter, parallel-group study, 109 pediatric patients with a history of endoscopically-proven GERD (1 to 11 years of age; 53 female; 89 Caucasian, 19 Black, 1 Other) were treated with NEXIUM once daily for up to 8 weeks to evaluate safety and tolerability. Dosing by patient weight was as follows:

Patients were endoscopically characterized as to the presence or absence of erosive esophagitis.

Of the 109 patients, 53 had erosive esophagitis at baseline (51 had mild, 1 moderate, and 1 severe esophagitis). Although most of the patients who had a follow up endoscopy at the end of 8 weeks of treatment healed, spontaneous healing cannot be ruled out because these patients had low grade erosive esophagitis prior to treatment, and the trial did not include a concomitant control.

12 to 17 Years of Age

In a multicenter, randomized, double-blind, parallel-group study, 149 adolescent patients (12 to 17 years of age; 89 female; 124 Caucasian, 15 Black, 10 Other) with clinically diagnosed GERD were treated with either NEXIUM 20 mg or NEXIUM 40 mg once daily for up to 8 weeks to evaluate safety and tolerability. Patients were not endoscopically characterized as to the presence or absence of erosive esophagitis.

 

Two multicenter, double-blind, placebo-controlled studies were conducted in patients at risk of developing gastric and/or duodenal ulcers associated with continuous use of non-selective and COX-2 selective NSAIDs. A total of 1429 patients were randomized across the 2 studies. Patients ranged in age from 19 to 89 (median age 66.0 years) with 70.7% female, 29.3% male, 82.9% Caucasian, 5.5% Black, 3.7% Asian, and 8.0% Others. At baseline, the patients in these studies were endoscopically confirmed not to have ulcers but were determined to be at risk for ulcer occurrence due to their age (≥60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years. Patients receiving NSAIDs and treated with NEXIUM 20 mg or 40 mg once-a-day experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks. See Table 11. No additional benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg. These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer due to the low incidence.

Table 11: Cumulative percentage of patients without gastric ulcers at 26 weeks:

Study	No. of Patients	Treatment Group	% of Patients Remaining Gastric Ulcer Free*
1	191 194 184	NEXIUM 20 mg NEXIUM 40 mg Placebo	95.4 96.7 88.2
2	267 271 257	NEXIUM 20 mg NEXIUM 40 mg Placebo	94.7 95.3 83.3

 

Triple Therapy (NEXIUM/amoxicillin/clarithromycin): Two multicenter, randomized, double-blind studies were conducted using a 10 day treatment regimen. The first study (191) compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193) compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily. H. pylori eradication rates, defined as at least two negative tests and no positive tests from CLOtest^®, histology and/or culture, at 4 weeks post-therapy were significantly higher in the NEXIUM plus amoxicillin and clarithromycin group than in the NEXIUM plus clarithromycin or NEXIUM alone group. The results are shown in Table 12:

Table 12: H. pylori Eradication Rates at 4 Weeks after 10 Day Treatment Regimen % of Patients Cured [95% Confidence Interval] (Number of Patients)

Study	Treatment Group	Per-Protocol*	Intent-to-Treat†
191	NEXIUM plus amoxicillin and clarithromycin	84%‡ [78, 89] (n=196)	77% p < 0.05 compared to NEXIUM plus clarithromycin. [71, 82] (n=233)
	NEXIUM plus clarithromycin	55% [48, 62] (n=187)	52% [45, 59] (n=215)
193	NEXIUM plus amoxicillin and clarithromycin	85%§ [74, 93] (n=67)	78% p < 0.05 compared to NEXIUM alone. [67, 87] (n=74)
	NEXIUM	5% [0, 23] (n=22)	4% [0, 21] (n=24)

The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment regimen in the NEXIUM plus amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60) respectively, in the 191 and 193 studies (per-protocol analysis).

 

In a multicenter, open-label dose-escalation study of 21 patients (15 males and 6 females, 18 Caucasian and 3 Black, mean age of 55.5 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, NEXIUM significantly inhibited gastric acid secretion. Initial dose was 40 mg twice daily in 19/21 patients and 80 mg twice daily in 2/21 patients. Total daily doses ranging from 80 mg to 240 mg for 12 months maintained gastric acid output below the target levels of 10 mEq/h in patients without prior gastric acid-reducing surgery and below 5 mEq/hr in patients with prior gastric acid-reducing surgery. At the Month 12 final visit, 18/20 (90%) patients had Basal Acid Output (BAO) under satisfactory control (median BAO = 0.17 mmol/hr). Of the 18 patients evaluated with a starting dose of 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit. See Table 13.

Table 13: Adequate Acid Suppression at Final Visit by Dose Regimen

NEXIUM dose at the Month 12 visit	BAO under adequate control at the Month 12 visit (N=20)*
40 mg twice daily	13/15
80 mg twice daily	4/4
80 mg three times daily	1/1

 

log-rank test vs. omeprazole 20 mgN.S. = not significant (p > 0.05)Defined as 7 consecutive days with no heartburn reported in daily patient diary.Defined as the cumulative proportion of patients who have reached the start of sustained resolutionlog-rank test vs. omeprazole 20 mgN.S. = not significant (p > 0.05)%= Life Table Estimate. Significant difference from placebo (p<0.01).Patients were included in the analysis if they had H. pylori infection documented at baseline, had at least one endoscopically verified duodenal ulcer ≥ 0.5 cm in diameter at baseline or had a documented history of duodenal ulcer disease within the past 5 years, and were not protocol violators. Patients who dropped out of the study due to an adverse reaction related to the study drug were included in the analysis as not H. pylori eradicated.Patients were included in the analysis if they had documented H. pylori infection at baseline, had at least one documented duodenal ulcer at baseline, or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts were included as not H. pylori eradicated. p < 0.05 compared to NEXIUM plus clarithromycin. p < 0.05 compared to NEXIUM alone.One patient was not evaluated.

 

HOW SUPPLIED

NEXIUM Delayed-Release Capsules, 20 mg, are opaque, hard gelatin, amethyst colored capsules with two radial bars in yellow on the cap and NEXIUM 20 mg in yellow on the body. They are supplied as follows:

NDC 0186-5020-31 unit of use bottles of 30

NDC 0186-5022-28 unit dose packages of 100

NDC 0186-5020-54 bottles of 90

NDC 0186-5020-82 bottles of 1000

NEXIUM Delayed-Release Capsules, 40 mg, are opaque, hard gelatin, amethyst colored capsules with three radial bars in yellow on the cap and NEXIUM 40 mg in yellow on the body. They are supplied as follows:

NDC 0186-5040-31 unit of use bottles of 30

NDC 0186-5042-28 unit dose packages of 100

NDC 0186-5040-54 bottles of 90

NDC 0186-5040-82 bottles of 1000

NDC 0186-5040-35 unit of use bottles of 30

NDC 0186-5042-25 unit dose packages of 100

NDC 0186-5040-55 bottles of 90

NDC 0186-5040-85 bottles of 1000

NEXIUM For Delayed-Release Oral Suspension is supplied as a unit dose packet containing a fine yellow powder, consisting of white to pale brownish esomeprazole granules and pale yellow inactive granules. NEXIUM unit dose packets are supplied as follows:

NDC 0186-4025-01 unit dose packages of 30: 2.5 mg packets

NDC 0186-4050-01 unit dose packages of 30: 5 mg packets

NDC 0186-4010–01 unit dose packages of 30: 10 mg packets

NDC 0186-4020–01 unit dose packages of 30: 20 mg packets

NDC 0186-4040–01 unit dose packages of 30: 40 mg packets

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). [See USP Controlled Room Temperature]. Keep NEXIUM Delayed-Release Capsules container tightly closed. Dispense in a tight container if the NEXIUM Delayed-Release Capsules product package is subdivided.

 

 

INFORMATION FOR PATIENTS

“See FDA-Approved Medication Guide”

see Drug Interactions (7.1) see Dosage and Administration (2)

Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.3)].

Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions (5.6) ].

Distributed by:

AstraZeneca LP

Wilmington, DE 19850

NEXIUM and the color purple as applied to the capsule are registered trademarks of the AstraZeneca group of companies.

©AstraZeneca 2012

Rev. 11/2012

 

 

SPL MEDGUIDE

NEXIUM^® (nex-e-um)

(esomeprazole magnesium)

Delayed-Release Capsules

NEXIUM^® (nex-e-um)

(esomeprazole magnesium)

For Delayed-Release
Oral Suspension

Read the Medication Guide that comes with NEXIUM before you start taking NEXIUM and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about NEXIUM?

NEXIUM may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

NEXIUM can cause serious side effects, including:

Diarrhea(Clostridium difficile)

Bone fractures

What are the possible side effects of NEXIUM

What is NEXIUM?

NEXIUM is a prescription medicine called a proton pump inhibitor (PPI). NEXIUM reduces the amount of acid in your stomach.

NEXIUM is used in adults:

For children and adolescents 1 year to 17 years of age, NEXIUM may be prescribed for up to 8 weeks for short-term treatment of GERD.

In children ages 1 month to less than 1 year of age, NEXIUM is only used to treat GERD with acid-related damage to the esophagus (erosive esophagitis) for up to 6 weeks.

It is not known if NEXIUM is effective in children under 1 month of age.

Who should not take NEXIUM?

Do not take NEXIUM if you:

What should I tell my doctor before taking NEXIUM?

Before you take NEXIUM, tell your doctor if you:

Tell your doctor about all of the medicines you take, including prescription and non-prescription drugs, vitamins and herbal supplements. NEXIUM may affect how other medicines work, and other medicines may affect how NEXIUM works.

How should I take NEXIUM?

Never chew or crush NEXIUM.

What are the possible side effects of NEXIUM?

NEXIUM can cause serious side effects, including:

What is the most important information I should know about NEXIUM?”Chronic (lasting a long time) inflammation of the stomach lining (Atrophic Gastritis)Low magnesium levels in your body.

Your doctor may check the level of magnesium in your body before you start taking NEXIUM or during treatment if you will be taking NEXIUM for a long period of time.

The most common side effects with NEXIUM may include:

Other side effects:

Serious allergic reactions. Tell your doctor if you get any of the following symptoms with NEXIUM:

Your doctor may stop NEXIUM if these symptoms happen.

Tell your doctor if you have any side effects that bother you or that do not go away. These are not all the possible side effects with NEXIUM.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store NEXIUM?

Keep NEXIUM and all medicines out of the reach of children.

General information about NEXIUM

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NEXIUM for a condition for which it was not prescribed. Do not give NEXIUM to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about NEXIUM. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about NEXIUM that is written for health professionals.

For more information, go to www.purplepill.com or call 1-800-463-9486.

What are the ingredients in NEXIUM?

Active ingredient: esomeprazole magnesium trihydrate

Inactive ingredients in NEXIUM Delayed-Release Capsules (including the capsule shells): glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, triethyl citrate, gelatin, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.

Inactive granules in NEXIUM For Delayed-Release Oral Suspension: dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose.

Instructions for Use

For instructions on taking Delayed-Release Capsules, see the section of this leaflet called “How should I take NEXIUM?”

Take NEXIUM For Delayed-Release Oral Suspension as follows:

NEXIUM Delayed-Release Capsules and NEXIUM For Delayed-Release Oral Suspension may be given through a nasogastric tube (NG tube) or gastric tube, as prescribed by your doctor. Follow the instructions below:

NEXIUM Delayed-Release Capsules:

NEXIUM For Delayed-Release Oral Suspension:

This Medication Guide has been approved by the U.S. Food and Drug Administration.

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

Issued November 2012

NEXIUM is a registered trademark of the AstraZeneca group of companies.

©2012 AstraZeneca Pharmaceuticals LP. All rights reserved

 

 

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

NEXIUM Esomeprazole magnesium CAPSULE, DELAYED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:52125-067(NDC:0186-5020) Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ESOMEPRAZOLE MAGNESIUM ESOMEPRAZOLE 20 mg Inactive Ingredients Ingredient Name Strength GLYCERYL MONOSTEARATE HYDROXYPROPYL CELLULOSE (TYPE H) HYPROMELLOSES MAGNESIUM STEARATE METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A talc TRIETHYL CITRATE polysorbate 80 GELATIN HYDROLYSATE (PORCINE SKIN, MW 3000) FD&C BLUE NO. 1 FD&C RED NO. 40 D&C RED NO. 28 titanium dioxide ALCOHOL, X-RAY EXPOSED (1000 RAD) ISOPROPYL ALCOHOL BUTYL ALCOHOL POLYETHYLENE GLYCOLS SODIUM HYDROXIDE POVIDONES D&C YELLOW NO. 10 POTASSIUM SORBATE WATER BUFFALO, COOKED ANHYDROUS DEXTROSE ANHYDROUS CITRIC ACID FERRIC OXIDE YELLOW Product Characteristics Color Size Imprint Code Shape purple 14 mm NEXIUM20mg CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:52125-067-02 30 in 1 BLISTER PACK Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021153 2013-02-22