esomeprazole magnesium 20 MG Delayed Release Oral Capsule
Generic Name: ESOMEPRAZOLE MAGNESIUM
Brand Name: Esomeprazole Magnesium
- Substance Name(s):
- ESOMEPRAZOLE MAGNESIUM
DRUG INTERACTIONS
7 May affect plasma levels of antiretroviral drugs – use with atazanavir and nelfinavir is not recommended; if saquinavir is used with esomeprazole magnesium, 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, digoxin and mycophenolate mofetil).
Patients treated with esomeprazole magnesium 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: Esomeprazole magnesium 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: Esomeprazole magnesium may increase serum levels of tacrolimus (7.5) Methotrexate: Esomeprazole magnesium 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 CYP2C19.
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%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8.
Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hour before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin 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 Cmax by 75%, and in Cmin 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 esomeprazole magnesium.
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 Due to its effects on gastric acid secretion, esomeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability.
Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole.
Esomeprazole is an enantiomer of omeprazole.
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects).
Co-administration 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.
Co-administration of omeprazole 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 and MMF.
Use esomeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].
7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
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, postmarketing 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 CYP2C19, the major esomeprazole metabolizing enzyme.
Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 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 esomeprazole magnesium with clopidogrel.
When using esomeprazole magnesium, consider use of alternative anti-platelet therapy [see Clinical Pharmacology (12.3)].
Omeprazole acts as an inhibitor of CYP2C19.
Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively.
Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4 to 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 CYP2C19 and CYP3A4, 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 (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6 % and 43.9%, respectively).
Avoid concomitant use of St.
John’s Wort or rifampin with esomeprazole magnesium.
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 (5.10) 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 (5.11)].
OVERDOSAGE
10 A single oral dose of esomeprazole at 510 mg/kg (about 124 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 esomeprazole magnesium 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 Dr.
Reddy’s at 1-888-375-3784.
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]-1H-benzimidazole-1-yl) magnesium trihydrate.
Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers.
(Initial U.S.
approval of esomeprazole magnesium: 2001).
Its molecular formula is (C17H18N3O3S)2Mg x 3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis.
The structural formula is: 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 Erosive Esophagitis The healing rates of esomeprazole magnesium 40 mg, esomeprazole magnesium 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 Level1 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 1log-rank test vs.
omeprazole 20 mg N.S.
= not significant (p > 0.05).
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 1 of Heartburn (Erosive Esophagitis Patients) Cumulative Percent2 with Sustained Resolution Study No.
of Patients Treatment Groups Day 14 Day 28 SignificanceLevel 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 1Defined as 7 consecutive days with no heartburn reported in daily patient diary.
2Defined as the cumulative proportion of patients who have reached the start of sustained resolution 3log-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 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 esomeprazole magnesium 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.
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) scheduled visit Figure 3: Maintenance of Healing Rates by Month (Study 178) scheduled visit Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis 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 erosive esophagitis was 93.7% for six months and 89.4% for one year.
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 esomeprazole magnesium 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 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.
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, esomeprazole magnesium 20 mg and 40 mg and omeprazole 20 mg were evaluated.
No significant treatment related differences were seen.
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 esomeprazole magnesium 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 esomeprazole magnesium 5 mg or 10 mg weight ≥20 kg: once daily treatment with esomeprazole magnesium 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 esomeprazole magnesium 20 mg or esomeprazole magnesium 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 years) with 70.7% female, 29.3% male, 82.9% Caucasian, 5.5% Black, 3.7% 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 (>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 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 esomeprazole magnesium 40 mg over esomeprazole magnesium 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 Free1 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).
14.5 Helicobacter pylori (H.
pylori) Eradication in Patients with Duodenal Ulcer Disease Triple Therapy (esomeprazole magnesium/amoxicillin/clarithromycin): Two multicenter, randomized, double-blind studies were conducted using a 10 day treatment regimen.
The first study (191) compared esomeprazole magnesium 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium 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 1000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium 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 esomeprazole magnesium plus amoxicillin and clarithromycin group than in the esomeprazole magnesium plus clarithromycin or esomeprazole magnesium 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-Protocol1 Intent-to-Treat 2 191 Esomeprazole magnesium plus amoxicillin and clarithromycin 84%3 [78, 89] (n=196) 77% [71, 82] (n=233) Esomeprazole magnesium plus clarithromycin 55% [48, 62] (n=187) 52% [45, 59] (n=215) 193 Esomeprazole magnesium plus 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.
2.
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.
3.
p < 0.05 compared to esomeprazole magnesium plus clarithromycin.
4.
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 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, esomeprazole magnesium 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 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 1One patient was not evaluated.
HOW SUPPLIED
16 /STORAGE AND HANDLING Esomeprazole magnesium delayed-release capsules USP, 20 mg are pale yellow to yellow 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 yellow 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 USP container tightly closed.
Dispense in a tight container if the esomeprazole magnesium delayed-release capsules USP product package is subdivided.
RECENT MAJOR CHANGES
Warnings and Precautions, Fundic Gland Polyps (5.12) 06/2018
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients who received esomeprazole magnesium 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 Esomeprazole magnesium delayed-release capsules USP, 20 mg are pale yellow to yellow 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 yellow 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 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 Esomeprazole magnesium delayed-release capsule USP 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 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 erosive esophagitis.
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.
In infants 1 month to less than 1 year, esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD.
Maintenance of Healing of Erosive Esophagitis Esomeprazole magnesium delayed-release capsules are indicated to maintain symptom resolution and healing of erosive esophagitis.
Controlled studies do not extend beyond 6 months.
Symptomatic Gastroesophageal Reflux Disease 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 and children 1 year or older.
1.2 Risk Reduction of 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 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 (esomeprazole magnesium delayed-release capsules plus amoxicillin and clarithromycin): Esomeprazole magnesium delayed-release capsules, in combination with amoxicillin and clarithromycin, are 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 Esomeprazole magnesium delayed-release capsule USP 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 esomeprazole magnesium 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 esomeprazole magnesium 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 esomeprazole magnesium have not been established in patients less than 1 month of age.
1 to 17 years of age Use of esomeprazole magnesium 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 Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Strudies (14.3) ].
The safety and effectiveness of esomeprazole magnesium 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 esomeprazole magnesium 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 Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Strudies (14.3) ].
Symptomatic GERD in infants 1 month to less than one year of age There was no statistically significant difference between esomeprazole magnesium 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 esomeprazole magnesium 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 esomeprazole magnesium 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 esomeprazole magnesium 1mg/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 esomeprazole magnesium in neonates the geometric mean (range) for the apparent clearance (CL/F) was 0.55 L/h/kg (0.25 to 1.6 L/h/kg).
The safety and effectiveness of esomeprazole magnesium in neonates have not been established.
Juvenile Animal Data 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 Teratogenic Effects: Risk Summary There are no adequate and well-controlled studies with esomeprazole magnesium 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.
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 H2 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 H2 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 H2-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 Interstitial Nephritis: Observedin patients taking PPIs.
(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) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue esomeprazole magnesium and refer to specialist for evaluation.
(5.5) Interaction with Clopidogrel: Avoid concomitant use of esomeprazole magnesium.
(5.6) Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.
(5.7) Hypomagnesemia: Reported rarely with prolonged treatment with PPIs.
(5.8) Interaction with St.
John’s Wort or Rifampin: Avoid concomitant use of esomeprazole magnesium.
(5.9, 7.3) 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.
(5.10, 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.
(5.11, 7.7) Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year.
Use the shortest duration of therapy.
(5.12) 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 Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including esomeprazole magnesium.
Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction.
Discontinue esomeprazole magnesium if acute interstitial nephritis develops [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 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.
5.6 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 (7.3) and Clinical Pharmacology (12.3)].
5.7 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.
5.8 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)] 5.9 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 (7.3)] Avoid concomitant use of esomeprazole magnesium with St.
John’s Wort, or rifampin.
5.10 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)].
5.11 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 (7.7)].
5.12 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).
Adverse Reactions Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with: • Hypersensitivity Reactions [see Contraindications (4) ] • Acute Interstitial Nephritis [see Warnings and Precautions (5.2) ] • Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3) ] • Bone Fracture [see Warnings and Precaution (5.4) ] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.5) ] • Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7) ] • Hypomagnesemia [see Warnings and Precautions (5.8) ] Drug Interactions • Advise patients to let you know if they are taking, or begin taking, other medications, because esomeprazole magnesium can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes [see Drug Interactions (7.1) ].
Administration • Let patients know that antacids may be used while taking esomeprazole magnesium delayed-release capsules.
• Advise patients to take esomeprazole magnesium delayed-release capsules at least one hour before a meal.
• For patients who are prescribed esomeprazole magnesium delayed-release capsules, advise them not to chew or crush the capsules.
• Advise patients that, if they open esomeprazole magnesium 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 esomeprazole magnesium delayed-release capsules before taking them, 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.
DOSAGE AND ADMINISTRATION
2 Esomeprazole magnesium is supplied as delayed-release capsules for oral administration.
The recommended dosages are outlined in Table 1.
Esomeprazole magnesium delayed-release capsules 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.
Table 1: Recommended Dosage Schedule for Esomeprazole Magnesium Delayed-Release Capsules Indication Dose Frequency Gastroesophageal Reflux Disease (GERD) Healing of Erosive Esophagitis 20 mg or 40 mg Once Daily for 4 to 8 Weeks1 Maintenance of Healing of Erosive Esophagitis 20 mg Once Daily2 Symptomatic Gastroesophageal Reflux Disease 20 mg Once Daily for 4 Weeks3 Pediatric GERD 12 to 17 Year Olds Healing of Erosive Esophagitis 20 mg or 40 mg Once Daily for 4 to 8 Weeks Symptomatic GERD 20 mg Once Daily for 4 Weeks 1 to 11 Year Olds4 Short-term Treatment of Symptomatic GERD 10 mg Once Daily for up to 8 Weeks Healing of Erosive Esophagitis weight < 20 kg 10 mg Once Daily for 8 Weeks weight ≥ 20 kg 10 mg or 20 mg Once 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 mg Once Daily for up to 6 months H.
pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Esomeprazole magnesium 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 Including Zollinger-Ellison Syndrome 40 mg6 Twice Daily7 1[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.
2Controlled studies did not extend beyond six months.
3If symptoms do not resolve completely after 4 weeks, an additional 4 weeks of treatment may be considered.
4Doses over 1 mg/kg/day have not been studied.
5 Doses over 1.33 mg/kg/day have not been studied.
6 The dosage of esomeprazole magnesium delayed-release capsules in patients with pathological hypersecretory conditions varies with the individual patient.
Dosage regimens should be adjusted to individual patient needs.
7 Doses up to 240 mg daily have been administered [see Drug Interactions (7) ] Please refer to amoxicillin and clarithromycin prescribing information for Contraindications, Warnings, and dosing in elderly and renally-impaired patients.
Indication Dose Frequency Gastroesophageal Reflux Disease (GERD) Adults 12 to 17 years 1 to 11 years 20 mg or 40mg 20 mg or 40 mg 10 mg or 20 mg Once daily for 4 to 8 weeks Once daily for up to 8 weeks 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 Pathological Hypersecretory Conditions 40 mg Twice daily H.
pylori Eradication (Triple Therapy): Esomeprazole magnesium Amoxicillin Clarithromycin 40 mg 1000 mg 500 mg Once daily for 10 days Twice daily for 10 days Twice daily for 10 days See full prescribing information for administration options (2) Patients with severe liver impairment-do not exceed dose of 20 mg (2) Specific 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 esomeprazole magnesium delayed-release capsules should not be exceeded [see Clinical Pharmacology (12.3)].
Directions for use specific to the route and available methods of administration for each of these dosage forms are presented in Table 2.
Table 2: Administration Options Administration Options (See text following table for additional instructions.) Dosage Form Route Options Delayed-Release Capsules Oral Capsule can be swallowed whole.
-or- Capsule can be opened and mixed with applesauce.
Delayed-Release Capsules Nasogastric Tube Capsule can be opened and the intact granules emptied into a syringe and delivered through the nasogastric tube.
Esomeprazole Magnesium Delayed-Release Capsules Esomeprazole magnesium 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 esomeprazole magnesium 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, esomeprazole magnesium 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 esomeprazole magnesium 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.