Esomeprazole 40 MG Delayed Release Oral Capsule

DRUG INTERACTIONS

7 May affect plasma levels of antiretroviral drugs – use with atazanavir and nelfinavir is not recommended; if saquinavir is used with NEXIUM, monitor for toxicity and consider saquinavir dose reduction ( 7.1) May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, erlotinib, and digoxin).

Patients treated with NEXIUM and digoxin may need to be monitored for digoxin toxicity.

( 7.2) Combined inhibitor of CYP 2C19 and 3A4 may raise esomeprazole levels ( 7.3) Clopidogrel: NEXIUM decreases exposure to the active metabolite of clopidogrel.

( 7.3) May increase systemic exposure of cilostazol and an active metabolite.

Consider dose reduction ( 7.3) Tacrolimus: NEXIUM may increase serum levels of tacrolimus ( 7.5) Methotrexate: NEXIUM may increase serum levels of methotrexate ( 7.7) 7.1 Interference with Antiretroviral Therapy 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.

7.2 Drugs for Which Gastric pH Can Affect Bioavailability Esomeprazole inhibits gastric acid secretion.

Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability.

Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole.

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects).

Esomeprazole is an enantiomer of omeprazole.

Coadministration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin.

Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole.

7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways Esomeprazole is extensively metabolized in the liver by CYP 2C19 and CYP 3A4.

In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4.

No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.

Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin, or amoxicillin.

However, post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy.

Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Esomeprazole may potentially interfere with CYP 2C19, the major esomeprazole metabolizing enzyme.

Coadministration of esomeprazole 30 mg and diazepam, a CYP 2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Clopidogrel 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.

7.4 Interactions with Investigations of Neuroendocrine Tumors 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) ] 7.5 Tacrolimus Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.

7.6 Combination Therapy with Clarithromycin 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].

7.7 Methotrexate 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) ].

OVERDOSAGE

10 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.

DESCRIPTION

11 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]-1 H-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 (C 17H 18N 3O 3S) 2Mg x 3 H 2O 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.

ChemStruc

CLINICAL STUDIES

14 14.1 Healing of Erosive Esophagitis 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 log-rank test vs.

omeprazole 20 mg 1 588 NEXIUM 20 mg 68.7% 90.6% N.S.

N.S.

= not significant (p > 0.05) 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.

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 Defined as 7 consecutive days with no heartburn reported in daily patient diary.

of Heartburn (Erosive Esophagitis Patients) Cumulative Percent Defined as the cumulative proportion of patients who have reached the start of sustained resolution with Sustained Resolution Study No.

of Patients Treatment Groups Day 14 Day 28 Significance Level log-rank test vs.

omeprazole 20 mg 1 573 NEXIUM 20 mg 64.3% 72.7% N.S.

N.S.

= not significant (p > 0.05) 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.

626 Omeprazole 20 mg 56.5% 66.6% 3 568 NEXIUM 40 mg 65.4% 73.9% N.S.

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.

Fig2 Fig3 14.2 Symptomatic Gastroesophageal Reflux Disease (GERD) 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.

Fig4 FIg5 14.3 Pediatric Gastroesophageal Reflux Disease (GERD) 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: weight < 20 kg: once daily treatment with NEXIUM 5 mg or 10 mg weight ≥ 20 kg: once daily treatment with NEXIUM 10 mg or 20 mg 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.

14.4 Risk Reduction of NSAID-Associated Gastric Ulcer 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 %= Life Table Estimate.

Significant difference from placebo (p<0.01).

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 14.5 Helicobacter pylori (H.pylori) Eradication in Patients with Duodenal Ulcer Disease 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 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.

Intent-to-Treat 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.

191 NEXIUM plus amoxicillin and clarithromycin 84% p < 0.05 compared to NEXIUM plus clarithromycin.

[78, 89] (n=196) 77% [71, 82] (n=233) NEXIUM plus clarithromycin 55% [48, 62] (n=187) 52% [45, 59] (n=215) 193 NEXIUM plus amoxicillin and clarithromycin 85% p < 0.05 compared to NEXIUM alone.

[74, 93] (n=67) 78% [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).

14.6 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 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) One patient was not evaluated.

40 mg twice daily 13/15 80 mg twice daily 4/4 80 mg three times daily 1/1

HOW SUPPLIED

16 /STORAGE AND HANDLING 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 58118-5040-3 bottles of 30 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.

RECENT MAJOR CHANGES

Recent Major Changes Warnings and Precautions, Interaction with Clopidogrel (5.4) 10/2012 Warnings and Precautions, Clostridium difficile associated diarrhea (5.3) 09/2012 Warnings and Precautions, Concomitant use of NEXIUM with Methotrexate (5.9) 01/2012 Indications and Usage, Treatment of GERD (1.1) 12/2011 Dosage and Administration (2) 12/2011

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients who received NEXIUM in clinical trials, 1459 were 65 to 74 years of age and 354 patients were ≥ 75 years of age.

No overall differences in safety and efficacy were observed between the elderly and younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 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 Delayed-Release Capsules: 20 mg and 40 mg ( 3) NEXIUM For Delayed-Release Oral Suspension: 2.5 mg, 5 mg, 10 mg, 20 mg, and 40 mg ( 3)

MECHANISM OF ACTION

12.1 Mechanism of Action 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.

INDICATIONS AND USAGE

1 NEXIUM is a proton pump inhibitor indicated for the following: Treatment of gastroesophageal reflux disease (GERD) (1.1) Risk reduction of NSAID-associated gastric ulcer (1.2) H.

pylori eradication to reduce the risk of duodenal ulcer recurrence (1.3) Pathological hypersecretory conditions, including Zollinger-Ellison syndrome (1.4) 1.1 Treatment of Gastroesophageal Reflux Disease (GERD) 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.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.

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.

1.2 Risk Reduction of NSAID-Associated Gastric Ulcer NEXIUM is indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in patients at risk for developing gastric ulcers.

Patients are considered to be at risk due to their age (≥ 60) and/or documented history of gastric ulcers.

Controlled studies do not extend beyond 6 months.

1.3 H.

pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence 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 ].

1.4 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome NEXIUM is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of NEXIUM have been established in pediatric patients 1 to 17 years of age for short-term treatment (up to eight weeks) of GERD.

The safety and effectiveness of NEXIUM have been established in pediatric patients 1 month to less than 1 year for short-term treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD.

However, the safety and effectiveness of NEXIUM have not been established in patients less than 1 month of age.

1 to 17 years of age 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.

PREGNANCY

8.1 Pregnancy 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.

NUSRING MOTHERS

8.3 Nursing Mothers Omeprazole concentrations have been measured in breast milk of one woman taking omeprazole 20 mg per day.

However, the excretion of esomeprazole in milk has not been studied.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for NEXIUM in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Symptomatic response does not preclude the presence of gastric malignancy.

( 5.1) Atrophic gastritis has been noted with long-term omeprazole therapy.

( 5.2) PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea.

( 5.3) Avoid concomitant use of NEXIUM with clopidogrel.

( 5.4) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine.

( 5.5) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs ( 5.6) Avoid concomitant use of NEXIUM with St John’s Wort or rifampin due to the potential reduction in esomeprazole levels ( 5.7) ( 7.3) Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors.

( 5.8, 12.2) 5.1 Concurrent Gastric Malignancy Symptomatic response to therapy with NEXIUM does not preclude the presence of gastric malignancy.

5.2 Atrophic Gastritis Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer.

5.3 Clostridium difficile associated diarrhea 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.

5.4 Interaction with Clopidogrel 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) ] 5.5 Bone Fracture 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) ] 5.6 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy.

Serious adverse events include tetany, arrhythmias, and seizures.

In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

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) ] 5.7 Concomitant use of NEXIUM with St John’s Wort or rifampin 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.

5.8 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity.

The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.

Providers should temporarily stop esomeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high.

If serial tests are performed (e.g.

for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

5.9 Concomitant use of NEXIUM with Methotrexate 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) ]

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION “See FDA-Approved Medication Guide” Advise patients to let you know if they are taking, or begin taking, other medications, because NEXIUM can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes [ see Drug Interactions (7.1) ].

Let patients know that antacids may be used while taking NEXIUM.

Advise patients to take NEXIUM at least one hour before a meal.

For patients who are prescribed NEXIUM Delayed-Release Capsules, advise them not to chew or crush the capsules.

Advise patients that, if they open NEXIUM Delayed-Release Capsules to mix the granules with food, the granules should only be mixed with applesauce.

Use with other foods has not been evaluated and is not recommended.

For patients who are advised to open the NEXIUM Delayed-Release Capsules before taking them or who are prescribed NEXIUM For Delayed-Release Oral Suspension, instruct them in the proper technique for administration [ see Dosage and Administration (2) ] and tell them to follow the dosing instructions in the PATIENT INFORMATION insert included in the package.

Instruct patients to rinse the syringe with water after each use.

For patients who are prescribed NEXIUM for Delayed-Release Oral Suspension and need to use more than one packet for their dose, instruct them regarding the correct amount of water to use when mixing their dose.

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

DOSAGE AND ADMINISTRATION

2 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.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.

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.

Table 1: Recommended Dosage Schedule of NEXIUM IndicationIndication DoseDose FrequencyFrequency Gastroesophageal Reflux Disease (GERD) Healing of Erosive EsophagitisHealing of Erosive Esophagitis 20 mg or 40 mg20 mg or 40 mg Once Daily for 4 to 8 Weeks Once Daily for 4 to 8 Weeks [ See Clinical Studies (14.1) ]The majority of patients are healed within 4 to 8 weeks.

For patients who do not heal after 4 to 8 weeks, an additional 4 to 8 weeks of treatment may be considered.

Maintenance of Healing of Erosive Esophagitis Maintenance of Healing of Erosive Esophagitis 20 mg 20 mg Once Daily Once Daily Controlled studies did not extend beyond six months.

Symptomatic Gastroesophageal Reflux DiseaseSymptomatic Gastroesophageal Reflux Disease 20 mg20 mg Once Daily for 4 Weeks Once Daily for 4 Weeks If symptoms do not resolve completely after 4 weeks, an additional 4 weeks of treatment may be considered.

Pediatric GERD 12 to 17 Year Olds Healing of Erosive Esophagitis Symptomatic GERD 20 mg or 40 mg 20 mg Once Daily for 4 to 8 Weeks Once Daily for 4 Weeks 1 to 11 Year Olds Doses over 1 mg/kg/day have not been studied.

Short-term Treatment of Symptomatic GERDShort-term Treatment of Symptomatic GERD 10 mg10 mg Once Daily for up to 8 WeeksOnce Daily for up to 8 Weeks Healing of Erosive EsophagitisHealing of Erosive Esophagitis weight < 20 kg weight < 20 kg 10 mg10 mg Once Daily for 8 WeeksOnce Daily for 8 Weeks weight ≥ 20 kgweight ≥ 20 kg 10 mg or 20 mg10 mg or 20 mg Once Daily for 8 WeeksOnce Daily for 8 Weeks 1 month to 5 kg to 7.5 kg 5 mg Once Daily for up to 6 Weeks weight >7.5 kg to 12 kg 10 mg Once Daily for up to 6 Weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg20 mg or 40 mg Once Daily for up to 6 months Once Daily for up to 6 months H.

pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: NEXIUMNEXIUM 40 mg40 mg Once Daily for 10 DaysOnce Daily for 10 Days AmoxicillinAmoxicillin 1000 mg1000 mg Twice Daily for 10 DaysTwice Daily for 10 Days ClarithromycinClarithromycin 500 mg500 mg Twice Daily for 10 DaysTwice Daily for 10 Days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 40 mg 40 mg The dosage of NEXIUM in patients with pathological hypersecretory conditions varies with the individual patient.

Dosage regimens should be adjusted to individual patient needs.

Twice Daily Doses up to 240 mg daily have been administered [ see Drug Interactions (7)].

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

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.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 Administration Options (See text following table for additional instructions.) Dosage Form Route Options Delayed-Release CapsulesDelayed-Release Capsules OralOral Capsule can be swallowed whole.Capsule can be swallowed whole.

-or–or- Capsule can be opened and mixed with applesauce.

Capsule can be opened and mixed with applesauce.

Delayed-Release CapsulesDelayed-Release Capsules Nasogastric TubeNasogastric Tube Capsule can be opened and the intact granules emptied into a syringe and delivered through the nasogastric tube.Capsule can be opened and the intact granules emptied into a syringe and delivered through the nasogastric tube.

For Delayed-Release Oral SuspensionFor Delayed-Release Oral Suspension Oral Oral For the 2.5 mg and 5 mg strengths, mix the contents of packet with 5 mL of water, leave 2 to 3 minutes to thicken, stir and drink within 30 minutes.

For the 2.5 mg and 5 mg strengths, mix the contents of packet with 5 mL of water, leave 2 to 3 minutes to thicken, stir and drink within 30 minutes.

For the 10 mg, 20 mg and 40 mg strengths, mix contents of packet with 15 mL of water, and follow the instructions above.For the 10 mg, 20 mg and 40 mg strengths, mix contents of packet with 15 mL of water, and follow the instructions above.

For Delayed-Release Oral SuspensionFor Delayed-Release Oral Suspension Nasogastric or Gastric TubeNasogastric or Gastric Tube For the 2.5 mg and 5 mg strengths, add 5 mL of water to a syringe and then add contents of packet.

Shake the syringe; leave 2 to 3 minutes to thicken.

Shake the syringe and inject through the nasogastric or gastric tube within 30 minutes.

For the 2.5 mg and 5 mg strengths, add 5 mL of water to a syringe and then add contents of packet.

Shake the syringe; leave 2 to 3 minutes to thicken.

Shake the syringe and inject through the nasogastric or gastric tube within 30 minutes.

For the 10 mg, 20 mg and 40 mg strengths, add 15 mL of water, and follow the instructions above.For the 10 mg, 20 mg and 40 mg strengths, add 15 mL of water, and follow the instructions above.

NEXIUM Delayed-Release Capsules NEXIUM Delayed-Release Capsules should be swallowed whole.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.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.

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.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:NEXIUM For Delayed-Release Oral Suspension should be administered as follows: Empty the contents of a 2.5 mg or 5 mg packet into a container containing 5 mL of water.

For the 10 mg, 20 mg, and 40 mg strengths, the contents of a packet should be emptied into a container containing 15 mL of water.

Stir.

Leave 2 to 3 minutes to thicken.

Stir and drink within 30 minutes.

If any medicine remains after drinking, add more water, stir, and drink immediately.

In cases where there is a need to use two packets, they may be mixed in a similar way by adding twice the required amount of water or follow the mixing instructions provided by your pharmacist or doctor.

For patients who have a nasogastric or gastric tube in place, NEXIUM For Delayed-Release Oral Suspension can 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: Add 5 mL of water to a catheter tipped syringe and then add the contents of a 2.5 mg or 5 mg NEXIUM packet.

For the 10 mg, 20 mg, and 40 mg strengths, the volume of water in the syringe should be 15 mL.

It is important to only use a catheter tipped syringe when administering NEXIUM through a nasogastric tube or gastric tube.

Immediately shake the syringe and leave 2 to 3 minutes to thicken.

Shake the syringe and inject through the nasogastric or gastric tube, French size 6 or larger, into the stomach within 30 minutes.

Refill the syringe with an equal amount of water (5 mL or 15 mL).

Shake and flush any remaining contents from the nasogastric or gastric tube into the stomach.

Indication Dose Frequency Gastroesophageal Reflux Disease (GERD) Adults 20 mg or 40 mg Once daily for 4 to 8 weeks 12 to 17 years 20 mg or 40 mg Once daily for up to 8 weeks 1 to 11 years 10 mg or 20 mg Once daily for up to 8 weeks 1 month to less than 1 year: 2.5 mg, 5 mg or 10 mg (based on weight).

Once daily, up to 6 weeks for erosive esophagitis (EE) due to acid-mediated GERD only.

Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg Once daily for up to 6 months H.

pylori Eradication (Triple Therapy): NEXIUM 40 mg Once daily for 10 days Amoxicillin 1000 mg Twice daily for 10 days Clarithromycin 500 mg Twice daily for 10 days Pathological Hypersecretory Conditions 40 mg Twice daily See full prescribing information for administration options (2) Patients with severe liver impairment-do not exceed dose of 20 mg (2)