Esomeprazole 20 MG Delayed Release Oral Capsule

Details

Generic Name: ESOMEPRAZOLE MAGNESIUM

Brand Name: Esomeprazole Magnesium

Substance Name(s):
ESOMEPRAZOLE MAGNESIUM

DRUG INTERACTIONS

7 Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with esomeprazole and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Esomeprazole and Interaction with Diagnostics Antiretrovirals Clinical Impact: Theeffect of PPIs on antiretroviral drugs is variable.

The clinical importance and the mechanisms behind theseinteractions are notalways known.

Decreased exposure of someantiretroviral drugs (e.g.,rilpivirine atazanavir, and nelfinavir) when used concomitantly with esomeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3 )].

Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole may increase toxicity [see Clinical Pharmacology ( 12.3 )].

There are other antiretroviral drugs which do not resultin clinically relevant interactions with esomeprazole.

Intervention: Rilpivirine-containing products: Concomitant use with esomeprazole magnesium is contraindicated [see Contraindications ( 4 )].

Atazanavir: See prescribing information for atazanavir fordosing information.

Nelfinavir: Avoid concomitant use with esomeprazole magnesium.

See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including esomeprazole, and warfarin concomitantly.

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

Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain the target INR range.

Methotrexate Clinical Impact: Concomitant use of esomeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.

No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.12 )].

Intervention: A temporary withdrawal of esomeprazole magnesium may be considered in some patients receiving high-dose methotrexate.

2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol) Clopidogrel Clinical Impact: Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3 )].

There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.

Intervention: Avoid concomitant use with esomeprazole magnesium.

Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.7 )].

Citalopram Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3 )].

Intervention: Limit the dose of citalopram to a maximum of 20 mg per day.

See prescribing information for citalopram.

Cilostazol Clinical Impact: Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3 )].

Intervention: Consider reducing the dose of cilostazol to 50 mg twice daily.

See prescribing information for cilostazol.

Digoxin Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3 )].

Intervention: Monitor digoxin concentrations and adjust the dose, if needed, to maintain therapeutic drug concentrations.

See prescribing information for digoxin.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.

Amoxicillin also has drug interactions.

Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

See Drug Interactions in prescribing information for amoxicillin.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH.

The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole magnesium and MMF.

Use esomeprazole magnesium with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3 )].

See the prescribing information for other drugs dependent on gastric pH for absorption.

Tacrolimus Clinical Impact: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

Intervention: Monitor tacrolimus whole blood concentrations and consider reducing the dose, if needed, to maintain therapeutic drug concentrations.

See prescribing information for tacrolimus.

Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity.

The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.11 ), Clinical Pharmacology ( 12.2 )].

Intervention: Discontinue esomeprazole magnesium at least 14 days 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.

Interaction with Secretin Stimulation Test Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.

Intervention: Discontinue esomeprazole magnesium 4 weeks prior to testing [see Clinical Pharmacology ( 12.2 )] False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening test for tetrahydrocannabinol (THC) in patients receiving PPIs.

Intervention: An alternative confirmatory method should be considered to verify positive results.

Table 4: Clinically Relevant Interactions Affecting Esomeprazole When Co-Administered with Other Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of esomeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3 )].

Intervention: St.

John’s Wort, rifampin: Avoid concomitant use with [see Warnings and Precautions ( 5.10 )].

Ritonavir-containing products: see prescribing information for specific drugs Voriconazole Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology ( 12.3 )].

Intervention: Dose adjustment of esomeprazole magnesium is not normally required.

However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dosage adjustment may be considered.

See prescribing information for voriconazole.

See full prescribing information for a list of clinically important drug interactions.

( 7 )

OVERDOSAGE

10 Manifestations in patients exposed to omeprazole, the racemic mixture, at doses up to 2,400 mg (120 times the usual recommended clinical dose) include confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen at recommended dosages.

See the full prescribing information for omeprazole for complete safety information.

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.

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

DESCRIPTION

11 The active ingredient in the proton pump inhibitor Esomeprazole Magnesium Delayed-Release Capsules USP for oral administration 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 17 H 18 N 3 O 3 S) 2 Mg x 3 H 2 O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis.

The structural formula is: The magnesium salt is a white to slightly cream or slightly yellow colored powder.

It contains 3 moles of water of solvation and is soluble in methanol.

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.

Esomeprazole magnesium is supplied in delayed-release capsules.

Each delayed-release capsule contains 20 mg, or 40 mg of esomeprazole (present as 22.3 mg, or 44.5 mg esomeprazole magnesium trihydrate USP) in the form of enteric-coated granules with the following inactive ingredients: glyceryl monostearate, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer, polysorbate 80, simethicone, sugar spheres, talc and triethyl citrate.

The capsule shells have the following inactive ingredients: gelatin, FD&C Blue #1, titanium dioxide, ammonia solution, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, propylene glycol, potassium hydroxide and shellac.

CLINICAL STUDIES

14 14.1 Healing of EE in Adults The healing rates of esomeprazole magnesium delayed-release capsules 40 mg, esomeprazole magnesium delayed-release capsules 20 mg, and omeprazole delayed-release capsules 20 mg (the approved dose for this indication) once daily were evaluated in adult patients with endoscopically diagnosed EE in four multicenter, double-blind, randomized studies.

The healing rates at Weeks 4 and 8 were evaluated and are shown in Table 11: Table 11: EE Healing Rate (Life-Table Analysis) in Adults with EE Treated with Esomeprazole Magnesium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies Study No.

of Patients Treatment Groups EE Healing Rates Significance Level 1 Week 4 Week 8 1 588 588 Esomeprazole magnesium 20 mg Omeprazole 20 mg 68.7% 69.5% 90.6% 88.3% N.S.

2 654 656 650 Esomeprazole magnesium 40 mg Esomeprazole magnesium 20 mg Omeprazole 20 mg 75.9% 70.5% 64.7% 94.1% 89.9% 86.9% p < 0.001 p< 0.05 3 576 572 Esomeprazole magnesium 40 mg Omeprazole 20 mg 71.5% 68.6% 92.2% 89.8% N.S.

4 1216 1209 Esomeprazole magnesium 40 mg Omeprazole 20 mg 81.7% 68.7% 93.7% 84.2% p < 0.001 N.S.

= not significant (p > 0.05).

1 log-rank test vs.

omeprazole 20 mg In these same studies of patients with EE, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in the Table 12: Table 12: Sustained Resolution1 of Heartburn in Adults with EE Treated with Esomeprazole Magnesium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies Study No.

of Patients Treatment Group Cumulative Percent 2 with Sustained Resolution Day 14 Day 28 Significance Level 3 1 573 555 Esomeprazole magnesium 20 mg Omeprazole 20 mg 64.3% 64.1% 72.7% 70.9% N.S.

2 621 620 626 Esomeprazole magnesium 40 mg Esomeprazole magnesium 20 mg Omeprazole 20 mg 64.8% 62.9% 56.5% 74.2% 70.1% 66.6% p <0.001 3 568 551 Esomeprazole magnesium 40 mg Omeprazole 20 mg 65.4% 65.5% 73.9% 73.1% N.S.

4 1187 1188 Esomeprazole magnesium 40 mg Omeprazole 20 mg 67.6% 62.5% 75.1% 70.8% p <0.001 1 Defined as 7 consecutive days with no heartburn reported in daily patient diary.

2 Defined as the cumulative proportion of patients who have reached the start of sustained resolution 3 log-rank test vs.

omeprazole 20 mg N.S.

= not significant (p > 0.05).

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 esomeprazole magnesium 40 mg, 7 to 8 days for esomeprazole magnesium 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of esomeprazole magnesium with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of EE.

14.2 Maintenance of Healing of EE in Adults Two multicenter, randomized, double-blind placebo-controlled 4-arm studies were conducted in adult patients with endoscopically confirmed, healed EE to evaluate esomeprazole magnesium delayed-release capsules 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 esomeprazole magnesium 40 mg over esomeprazole magnesium 20 mg.

Esomeprazole magnesium delayed-release capsules 40 mg once daily is not a recommended regimen for the maintenance of healing of EE in adults.

The percentages of patients that maintained healing of EE at the various time points are shown in the Figures 2 and 3: Figure 2: Maintenance of Healing Rates of EE in Adults by Month (Study 177) s= scheduled visit Figure 3: Maintenance of EE Healing Rates in Adults by Month (Study 178) s= scheduled visit Patients remained in remission significantly longer and the number of recurrences of EE was significantly less in patients treated with esomeprazole magnesium compared to placebo.

In both studies, the proportion of patients on esomeprazole magnesium 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 esomeprazole magnesium 40 mg, the percentage of patients that maintained healing of EE was 93.7% for six months and 89.4% for one year.

14.3 Symptomatic GERD in Adults Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 adult patients comparing four weeks of treatment with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms.

Patients had at least a 6-month history of heartburn episodes, no EE 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 esomeprazole magnesium groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).

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

Esomeprazole magnesium 40 mg once daily is not a recommended regimen for the treatment of symptomatic GERD in adults.

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: Pe rcent of Patients Symptom-Free of Heartburn by Day (Study 226) In three European symptomatic GERD trials, esomeprazole magnesium 20 mg and 40 mg and omeprazole 20 mg were evaluated.

No significant treatment related differences were seen.

14.4 Pediatric GERD 12 Years 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 esomeprazole magnesium delayed-release capsules 20 mg or 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 EE.

14.5 Risk Reduction of NSAID-Associated Gastric Ulcer Two multicenter, double-blind, placebo-controlled studies were conducted in adult 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 1,429 patients were randomized across the 2 studies.

Patients ranged in age from 19 to 89 (median age 66 years) with 71% female, 29% male, 83% Caucasian, 5% Black, 4% Asian, and 8% 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 (at least 60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years.

Patients receiving NSAIDs and treated with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks.

See Table 13.

No additional benefit was seen with esomeprazole magnesium 40 mg over esomeprazole magnesium 20 mg.

Esomeprazole magnesium 40 mg once daily is not a recommended regimen for the risk reduction of NSAID-associated gastric ulcer in adults.

These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer due to the low incidence.

Table 13: Cumulative Percentage of Patients at Least 60 Years of Age Taking NSAIDS Without Gastric Ulcers at 26 Weeks in Two Randomized Placebo-Controlled Studies Study No.

of Patients Treatment Group % of Patients Remaining Gastric Ulcer Free 1 1 191 194 184 Esomeprazole magnesium 20 mg Esomeprazole magnesium 40 mg Placebo 95.4 96.7 88.2 2 267 271 257 Esomeprazole magnesium 20 mg Esomeprazole magnesium 40 mg Placebo 94.7 95.3 83.3 1 %= Life Table Estimate.

Significant difference from placebo (p<0.01).

14.6 H.

pylori Eradication in Adult Patients with Duodenal Ulcer Disease Two multicenter, randomized, double-blind studies were conducted in adult patients using a 10- day treatment regimen of triple therapy (esomeprazole magnesium, amoxicillin and clarithromycin).

The first study (191) compared esomeprazole magnesium delayed-release capsules 40 mg once daily in combination with amoxicillin 1,000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium delayed-release capsules 40 mg once daily plus clarithromycin 500 mg twice daily.

The second study (193) compared esomeprazole magnesium 40 mg once daily in combination with amoxicillin 1,000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium delayed-release capsules 40 mg once daily.

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 esomeprazole magnesium, amoxicillin and clarithromycin group than in the esomeprazole magnesium and clarithromycin group or the esomeprazole magnesium alone group.

The results are shown in Table 14: Table 14: H.

pylori Eradication Rates at 4 Weeks after 10 Day Treatment Regimen % of Adult Patients Cured [95% Confidence Interval] (Number of Patients) Study Treatment Group Per-Protocol 1 Intent-to-Treat 2 191 Esomeprazole magnesium, amoxicillin and clarithromycin 84% 3 [78, 89] (n=196) 77% [71, 82] (n=233) Esomeprazole magnesium, clarithromycin 55% [48, 62](n=187) 52% [45, 59] (n=215) 193 Esomeprazole magnesium, amoxicillin and clarithromycin 85% [74, 93](n=67) 78% 4 [67, 87] (n=74) Esomeprazole magnesium 5% [0, 23](n=22) 4% [0, 21](n=24) 1.

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 esomeprazole magnesium plus clarithromycin.

p < 0.05 compared to esomeprazole magnesium alone.

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

14.7 Pathological Hypersecretory Conditions, Including Zollinger- Ellison Syndrome, in Adults In a multicenter, open-label dose-escalation study of 21 adult patients (15 males and 6 females, 18 Caucasian and 3 Black, mean age of 56 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, esomeprazole magnesium significantly inhibited gastric acid secretion.

The initial dosage of esomeprazole magnesium delayed-release capsules was 40 mg twice daily in 19 patients and 80 mg twice daily in 2 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 esomeprazole magnesium 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit.

See Table 15.

Table 15: Adequate Acid Suppression at Final Visit by Dosage Regimen in Adult Patients with Pathological Hypersecretory Conditions Esomeprazole magnesium dose at the Month 12 visit BAO under adequate control at the Month 12 visit (N=20) 1 40 mg twice daily 13/15 80 mg twice daily 4/4 80 mg three times daily 1/1 1 One patient was not evaluated.

HOW SUPPLIED

16 /STORAGE AND HANDLING Esomeprazole magnesium delayed-release capsules USP, 20 mg are pale yellow to brown colored pellets filled in Size ‘4’ empty hard gelatin capsule shell with light blue cap and dark blue body imprinted with ‘RDY’ on cap and ‘492’ on body with black ink and are supplied in bottles of 30’s, 90’s and 1000’s.

Bottles of 30 NDC 43598-509-30 Bottles of 90 NDC 43598-509-90 Bottles of 1000 NDC 43598-509-10 Esomeprazole magnesium delayed-release capsules USP, 40 mg are pale yellow to brown colored pellets filled in Size ‘3’ empty hard gelatin capsule shell with light blue cap and dark blue body imprinted with ‘RDY’ on cap and ‘493’ on body with black ink and are supplied in bottles of 30’s, 90’s and 1000’s.

Bottles of 30 NDC 43598-510-30 Bottles of 90 NDC 43598-510-90 Bottles of 1000 NDC 43598-510-10 Store at 20°-25°C (68°-77°F).

[See USP Controlled Room Temperature].

Keep esomeprazole magnesium delayed-release capsules container tightly closed.

Dispense in a tight container if the esomeprazole magnesium delayed-release capsules product package is subdivided.

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients who received esomeprazole magnesium in clinical trials, 1,459 were 65 to 74 years of age and 354 patients were 75 years of age and older.

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 elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Esomeprazole magnesium delayed-release capsules Esomeprazole magnesium delayed-release capsules USP, 20 mg are pale yellow to brown colored pellets filled in Size ‘4’ empty hard gelatin capsule shell with light blue cap and dark blue body imprinted with ‘RDY’ on cap and ‘492’ on body with black ink.

Esomeprazole magnesium delayed-release capsules USP, 40 mg pale yellow to brown colored pellets filled in Size ‘3’ empty hard gelatin capsule shell with light blue cap and dark blue body imprinted with ‘RDY’ on cap and ‘493’ on body with black ink.

Esomeprazole magnesium Delayed-Release Capsules: 20 mg and 40 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Esomeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell.

Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide.

Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production.

This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

INDICATIONS AND USAGE

1 Esomeprazole magnesium is a proton pump inhibitor (PPI).

Esomeprazole magnesium delayed-release capsules are indicated for the: Short-term treatment in the healing of erosive esophagitis (EE) in adults and pediatric patients 12 years to 17 years of age.

( 1.1 ) Maintenance of healing of EE in adults.

( 1.2 ) Short-term treatment of heartburn and other symptoms associated GERD in adults and pediatric patients 12 years to 17 years of age.

( 1.3 ) Risk reduction of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults at risk for developing gastric ulcers due to age (60 years and older) and/or documented history of gastric ulcers.

( 1.4 ) Helicobacter pylori eradication in adult patients to reduce the risk of duodenal ulcer recurrence in combination with amoxicillin and clarithromycin.

( 1.5 ) Long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome in adults.

( 1.6 ) 1.1 Healing of Erosive Esophagitis (EE) Adults Esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed EE in adults.

For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4 to 8 week course of esomeprazole magnesium delayed-release capsules may be considered.

Pediatric Patients 12 Years to 17 Years of Age Esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 to 8 weeks) for the healing of EE in pediatric patients 12 years to 17 years of age.

1.2 Maintenance of Healing of EE Esomeprazole magnesium delayed-release capsules are indicated for the maintenance of healing of EE in adults.

Controlled studies do not extend beyond 6 months.

1.3 Treatment of Symptomatic GERD Adults Esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults.

Pediatric Patients 12 Years to 17 Years of Age Esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 12 years to 17 years of age.

1.4 Risk Reduction of Nonsteroidal Anti-Inflammatory Drugs (NSAID)-Associated Gastric Ulcer Esomeprazole magnesium delayed-release capsules are indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in adult patients at risk for developing gastric ulcers.

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

Controlled studies do not extend beyond 6 months.

1.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Eradication of H.pylori has been shown to reduce the risk of duodenal ulcer recurrence.

Triple Therapy Esomeprazole magnesium delayed-release capsules, in combination with amoxicillin and clarithromycin, are indicated for the treatment of adult patients with H.

pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H.

pylori .

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 clarithromyci n].

1.6 Pathological Hypersecretory Conditions Including Zollinger- Ellison Syndrome Esomeprazole magnesium delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome, in adults.

PEDIATRIC USE

8.4 Pediatric Use Healing of EE Pediatric Patients 1 Year to 17 Years of Age The safety and effectiveness of esomeprazole magnesium delayed-release capsules have been established in pediatric patients 12 years to 17 years for short-term treatment (4 to 8 weeks) for healing of EE.

Use of esomeprazole magnesium for this indication is supported by evidence from adequate and well-controlled studies in adults with additional safety and pharmacokinetic data in pediatric patients 1 year to 17 years of age.

The safety profile in pediatric patients 1 year to 17 years of age was similar to adults [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.4 )].

Symptomatic GERD Pediatric Patients 1 Year to 17 Years of Age The safety and effectiveness of esomeprazole magnesium delayed-release capsules have been established in pediatric patients 12 years to 17 years of age for the short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD.

The safety profile in pediatric patients 1 year to 17 years of age was similar to adults [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.4 )].

The safety and effectiveness of esomeprazole magnesium for the treatment of symptomatic GERD in pediatric patients less than 1 year of age have not been established.

Other Conditions The safety and effectiveness of esomeprazole magnesium delayed-release capsules for the risk reduction of NSAID-associated gastric ulcer, H.

pylori eradication to reduce the risk of duodenal ulcer recurrence and treatment of pathological hypersecretory conditions have not been established in pediatric patients.

Juvenile Animal Toxicity Studies In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area.

Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology ( 13.2) ].

PREGNANCY

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with esomeprazole in pregnant women.

Esomeprazole is the S-isomer of omeprazole.

Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use (see Data).

Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person).

Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis for a 60 kg person).

Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg.

When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age (see Data).

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data Esomeprazole is the S-isomer of omeprazole.

Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H 2 receptor antagonists or other controls.

A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 1999, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy.

The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population.

The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population.

A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor.

The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester.

A retrospective cohort study reported on 689 pregnant women exposed to either H 2 blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester.

The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H 2 -blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively.

A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures).

The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease paired controls.

Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.

Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.

Animal Data Omeprazole Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis 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 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis 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 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis), administered prior to mating through the lactation period.

Esomeprazole No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 41 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis.

A pre-and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis).

Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis).

Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis).

In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis).

Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis).

Effects on maternal bone were observed in pregnant and lactating rats in a pre-and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis).

When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis).

A pre-and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.

A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition.

When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Gastric Malignancy :In adults, symptomatic response does not preclude the presence of gastric malignancy.

Consider additional follow-up and diagnostic testing.

(5.1) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients.

(5.2) Clostridium difficile-Associated Diarrhea : PPI therapy may be associated with increased risk (5.3) 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.

(5.4) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

(5.5 ) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue esomeprazole magnesium and refer to specialist for evaluation.

(5.6) Interaction with Clopidogrel: Avoid concomitant use of esomeprazole magnesium.

(5.7) Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.

(5.8) Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged treatment with PPIs.

(5.9) Interaction with St.

John’s Wort or Rifampin: Avoid concomitant use of esomeprazole magnesium.

( 5.10 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increased chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors, temporarily stop esomeprazole magnesium at least 14 days before assessing CgA levels.

( 5.11 , 12.2 ) Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity.

With high dose methotrexate administration, consider temporary withdrawal of esomeprazole magnesium.

( 5.12 , 7 ) Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year.

Use the shortest duration of therapy.

(5.13) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with esomeprazole magnesium does not preclude the presence of gastric malignancy.

Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI.

In older patients, also consider an endoscopy.

5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy.

Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to nonspecific symptoms of decreased renal function (e.g., malaise, nausea, anorexia).

In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia).

Discontinue esomeprazole magnesium and evaluate patients with suspected acute TIN [see Contraindications ( 4 )].

5.3 Clostridium difficile – Associated Diarrhea Published observational studies suggest that PPI therapy like esomeprazole magnesium 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 difficile -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 esomeprazole magnesium, refer to Warnings and Precautions section of the corresponding prescribing information.

5.4 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) ].

5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions ( 6.2 )].

Discontinue esomeprazole magnesium at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole.

These events have occurred as both new onset and an exacerbation of existing autoimmune disease.

The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly.

Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs.

PPI associated SLE is usually milder than non-drug induced SLE.

Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly.

The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated.

If signs or symptoms consistent with CLE or SLE are noted in patients receiving esomeprazole magnesium, discontinue the drug and refer the patient to the appropriate specialist for evaluation.

Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks.

Serological testing (e.g.

ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7 Interaction with Clopidogrel Avoid concomitant use of esomeprazole magnesium 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 esomeprazole magnesium consider alternative anti-platelet therapy [see Drug Interactions ( 7 )].

5.8 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo-or achlorhydria.

Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature.

This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

5.9 Hypomagnesemia and Mineral Metabolism 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.

Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.

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 )] Consider monitoring magnesium and calcium levels prior to initiation of esomeprazole and magnesium and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism).

Supplement with magnesium and/or calcium, as necessary.

If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.10 Interaction 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 )].

Avoid concomitant use of esomeprazole magnesium with St.

John’s Wort, or rifampin.

5.11 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.

Healthcare providers should temporarily stop esomeprazole treatment at least 14 days 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 [see Clinical Pharmacology (12.2 )].

5.12 Interaction 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 )].

5.13 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.

Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy.

Use the shortest duration of PPI therapy appropriate to the condition being treated.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Acute Tubulointerstitial Nephritis Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with suspected acute TIN [see Warnings and Precautions ( 5.2 )].

Clostridium difficile-Associated Diarrhea Advise the patient or caregiver to immediately call the patient’s healthcare provider if they experience diarrhea that does not improve [see Warnings and Precautions ( 5.3 )].

Bone Fracture Advise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient’s healthcare provider [see Warnings and Precautions ( 5.4) ].

Severe Cutaneous Adverse Reactions Advise the patient or caregiver to discontinue esomeprazole magnesium delayed-release capsules and immediately call the patient’s healthcare provider for at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity signs or symptoms associated with Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.5 )].

Cutaneous and Systemic Lupus Erythematosus Advise the patient or caregiver to immediately call the patient’s healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions ( 5.6 )].

Cyanocobalamin (Vitamin B-12) Deficiency Advise the patient or caregiver to report any clinical symptoms that may be associated with cyanocobalamin deficiency to the patient’s healthcare provider if they have been receiving esomeprazole magnesium delayed-release capsules for longer than 3 years [see Warnings and Precautions ( 5.8 )].

Hypomagnesemia and Mineral Metabolism Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to the patient’s healthcare provider, if they have been receiving esomeprazole magnesium delayed-release capsules for at least 3 months [see Warnings and Precautions ( 5.9 )].

Drug Interactions Advise the patient or caregiver to report to their healthcare provider if starting treatment with rilpivirine-containing products, clopidogrel, St.

John’s Wort or rifampin; or, if they take high-dose methotrexate [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 , 5.10 , 5.12 )].

Administration Take esomeprazole magnesium delayed-release capsules at least one hour before meals.

Antacids may be used concomitantly with esomeprazole magnesium delayed-release capsules.

Swallow esomeprazole magnesium delayed-release capsules whole; do not chew or crush the capsules.

For patients who have difficulty swallowing capsules, esomeprazole magnesium delayed-release capsules can be opened, and the contents sprinkled on applesauce.

Use with other foods is not recommended.

Add one tablespoon of applesauce to an empty bowl.

The applesauce used should not be hot and should be soft enough to be swallowed without chewing.

Open the esomeprazole magnesium delayed-release capsule and carefully empty the granules inside the capsule onto the applesauce.

Mix the granules with the applesauce.

Administer the mixture immediately.

Do not chew or crush the granules 5.

Discard any remaining mixture.

Do not store the mixture for future use.

Esomeprazole magnesium delayed-release capsules can also be administered via a nasogastric tube, as described in the Instructions for Use.

Dispense with Medication Guide available at: www.drreddys.com/medguide/esomeprazolecaps.pdf Rx only Manufactured by: Dr.

Reddy’s Laboratories Limited Bachupally – 500 090 INDIA Revised: 07/2023

DOSAGE AND ADMINISTRATION

2 Population Recommended Adult ( 2.1 ) and Pediatric Dosage ( 2.2 ) Healing of EE (1 year and older) Adults 20 mg or 40 mg 1 once daily for 4 to 8 weeks; some patients may require an additional 4 to 8 weeks 12 years to 17 years 20 mg or 40 mg1 once daily for 4 to 8 weeks Maintenance of Healing of EE Adults 20 mg once daily.

Controlled studies do not extend beyond 6 months Treatment of Symptomatic GERD Adults 20 mg once daily once daily for 4 weeks some patients may require an additional 4 weeks 12 years to 17 years 20 mg once daily for 4 weeks Risk Reduction of NSAID-Associated Gastric Ulcer Adults 20 mg or 40 mg 1 once daily for up to 6 months2 H.

pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Adults Esomeprazole magnesium delayed-release capsules 40 mg 1 once daily for 10 days Amoxicillin 1000 mg twice daily for 10 days 3 Clarithromycin 500 mg twice daily for 10 days 3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Adults Starting dosage is 40 mg twice daily 4 (varies with the individual patient) as long as clinically indicated.

1 A maximum dosage of 20 mg once daily is recommended for patients with severe liver impairment (Child-Pugh Class C).

2 Controlled studies do not extend beyond 6 months.

3 Refer to the amoxicillin and clarithromycin prescribing information for dosage adjustments in elderly and renally-impaired patients.

4 A starting dosage of 20 mg twice daily is recommended for patients with severe liver impairment (Child-Pugh Class C).

Preparation and Administration Information Swallow capsules whole; do not crush or chew.

For patients who cannot swallow intact capsule, the capsule can be opened, and the contents mixed with applesauce.

( 2.3 ) Opened capsules can be administered through a nasogastric tube.

( 2.3 ) 2.1 Recommended Dosage in Adults by Indication Table 1 shows the recommended adult dosage of esomeprazole magnesium delayed-release capsules by indication.

The duration of esomeprazole magnesium delayed-release capsules treatment should be based on available safety and efficacy data specific to the defined indication and dosing frequency and individual patient medical needs.

Esomeprazole magnesium delayed-release capsules should only be initiated and continued if the benefits outweigh the risks of treatment.

Table 1: Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules in Adults by Indication Adult Indication Recommended Dosage of Esomeprazole magnesium delayed-release capsules Treatment Duration Healing of EE 20 mg or 40 mg 1 once daily 4 to 8 weeks 2 Maintenance of Healing of EE 20 mg once daily Controlled studies do not extend beyond 6 months Treatment of Symptomatic GERD 20 mg once daily 4 weeks; if symptoms do not resolve completely, consider an additional 4 weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg 1 once daily Controlled studies do not extend beyond 6 months H.

pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (Triple Therapy) Esomeprazole 40 mg once daily 1 10 days Amoxicillin 1000 mg twice daily 3 10 days Clarithromycin 500 mg twice daily 3 10 days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Starting dosage is 40 mg twice daily 4 ; individualize the regimen to patient needs.

Dosages of up to 240 mg/day have been administered [see Clinical Studies (14.7)] As long as clinically indicated 1.

A maximum dosage of 20 mg once daily is recommended for patients with severe liver impairment (Child-Pugh Class C) [see Use in Specific Populations ( 8.6 )].

Most 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 required to achieve healing [see Clinical Studies ( 14.1 )].

Refer to the amoxicillin and clarithromycin prescribing information for dosage adjustments in elderly and renally-impaired patients.

A starting dosage of 20 mg twice daily is recommended for patients with severe liver impairment (Child-Pugh Class C) [see Use in Specific Populations ( 8.6 )].

2.2 Recommended Dosage in Pediatric Patients by Indication Table 2 shows the recommended dosage of esomeprazole magnesium delayed-release capsules in pediatric patients by indication.

Table 2: Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules in Pediatric Patients by Indication Indication Patient Age Recommended Dosage Duration Healing of EE 12 years to 17 years Esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily 4 to 8 Weeks Treatment of Symptomatic GERD 12 years to 17 years Esomeprazole magnesium delayed-release capsules 20 mg once daily 4 weeks 1 Dosages over 1 mg/kg/day have not been studied 2 Dosages over 1.33 mg/kg/day have not been studied 2.3 Preparation and Administration Instructions Take esomeprazole magnesium delayed-release capsules at least one hour before meals [see Clinical Pharmacology ( 12.3 )].

Antacids may be used concomitantly with esomeprazole magnesium delayed-release capsules.

Take a missed dose as soon as possible.

If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time.

Do not take 2 doses at the same time.

Esomeprazole Magnesium Delayed-Release Capsules Administer esomeprazole magnesium delayed-release capsules orally or via a nasogastric tube, as described below.

Oral Administration Swallow esomeprazole magnesium delayed-release capsules whole; do not chew or crush the capsules.

For patients who have difficulty swallowing capsules, esomeprazole magnesium delayed-release capsules can be opened, and the contents sprinkled on applesauce.

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

Add one tablespoon of applesauce to an empty bowl.

The applesauce used should not be hot and should be soft enough to be swallowed without chewing.

Open the esomeprazole magnesium delayed-release capsule and carefully empty the granules inside the capsule onto the applesauce.

Mix the granules with the applesauce.

Administer the mixture immediately.

Do not chew or crush the granules 5.

Discard any remaining mixture.

Do not store the mixture for future use.

Administration via Nasogastric Tube 1.

Open the esomeprazole magnesium delayed-release capsule and empty the granules into a 60 mL catheter-tipped syringe.

Mix the granules with 50 mL of water.

Replace the plunger and shake the catheter-tipped syringe vigorously for 15 seconds.

Hold the catheter-tipped syringe with the tip up and check for any granules remaining in the tip.

Attach the catheter-tipped syringe to a nasogastric tube and deliver the contents of the syringe through the nasogastric tube into the stomach.

After administering the granules, flush the nasogastric tube with additional water.

Use the mixture immediately after preparation.

Do not administer the granules if they have dissolved or disintegrated.