Esomeprazole 20 MG Injection
DRUG INTERACTIONS
7 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.
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.
Increased plasma levels of diazepam were observed 12 hours after dosing and onwards.
However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance.
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 sodium with clopidogrel.
When using esomeprazole sodium, 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 C max and AUC of cilostazol by 18% and 26%, respectively.
C max 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.
Coadministration 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 for the recommended doses.
However, in patients who may require higher doses, dose adjustment may be considered.
Drugs known to induce CYP2C19 or CYP3A4 (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 metabolizers (C max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C max and AUC decreased by 49.6% and 43.9%, respectively).
Avoid concomitant use of St.
John’s Wort or rifampin with esomeprazole sodium.
Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole.
Concomitant use of atazanavir and proton pump inhibitors is not recommended.
Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.
Omeprazole 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.
For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole.
Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75%, respectively, for nelfinavir and M8.
Following multiple doses of atazanavir (400 mg daily) and omeprazole (40 mg daily, 2 hr before atazanavir), AUC was decreased by 94%, C max by 96%, and C min by 95%.
Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.
For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in C max by 75% and in C min by 106% following multiple dosing of saquinavir/ritonavir (1,000 mg/100 mg) twice daily for 15 days with omeprazole 40 mg daily coadministered days 11 to 15.
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.
Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of esomeprazole or these NSAIDs.
Esomeprazole inhibits gastric acid secretion.
Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability.
Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole.
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects).
Esomeprazole is an enantiomer of omeprazole.
Coadministration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin.
Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole.
Esomeprazole inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g.
ketoconazole, iron salts, erlotinib, and digoxin).
Patients treated with esomeprazole and digoxin may need to be monitored for digoxin toxicity.
( 7 ) Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
( 7 ) Esomeprazole may reduce the plasma levels of atazanavir, nelfinavir, and saquinavir.
( 7 ) Concomitant treatment with a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure.
( 7 ) May increase systemic exposure of cilostazol and an active metabolite.
Consider dose reduction.
( 7 ) Clopidogrel: Esomeprazole decreases exposure to the active metabolite of clopidogrel.
( 7 ) Tacrolimus: Esomeprazole may increase serum levels of tacrolimus ( 7.2 ) Methotrexate: Esomeprazole may increase serum levels of methotrexate ( 7.3 ) 7.1 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 (5.8) , Clinical Pharmacology (12.2) ].
7.2 Tacrolimus Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.
7.3 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 (5.9) ].
OVERDOSAGE
10 The minimum lethal dose of esomeprazole sodium in rats after bolus administration was 310 mg/kg (about 62 times the human dose on a body surface area basis).
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 overdose (limited experience of doses in excess of 240 mg/day) are transient.
Single oral doses of 80 mg and intravenous doses of 308 mg of esomeprazole over 24 hours 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, a certified Regional Poison Control Center should be contacted.
Telephone numbers are listed in the Physicians’ Desk Reference (PDR) or local telephone book.
DESCRIPTION
11 The active ingredient in esomeprazole sodium for injection is ( S )-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H -benzimidazole sodium, a proton pump inhibitor that inhibits gastric acid secretion.
Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers.
Its molecular formula is C 17 H 18 N 3 O 3 SNa with molecular weight of 367.4 g/mol (sodium salt) and 345.4 g/mol (parent compound).
Esomeprazole sodium is freely soluble in water.
The structural formula is: Esomeprazole sodium for injection is supplied as sterile, freeze-dried, white to off-white, porous cake or powder in a 5 mL vial, intended for intravenous administration after reconstitution with 0.9% Sodium Chloride Injection, USP; Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP.
Esomeprazole sodium for injection contains esomeprazole sodium 21.3 mg or 42.5 mg equivalent to esomeprazole 20 mg or 40 mg, edetate disodium 1.5 mg and sodium hydroxide q.s.
for pH adjustment.
The pH of reconstituted solution of esomeprazole sodium for injection depends on the reconstitution volume and is in the pH range of 9 to 11.
The stability of esomeprazole sodium in aqueous solution is strongly pH dependent.
The rate of degradation increases with decreasing pH.
chemical-structure
CLINICAL STUDIES
14 14.1 Acid Suppression in Gastroesophageal Reflux Disease (GERD) Four multicenter, open-label, two-period crossover studies were conducted to compare the pharmacodynamic efficacy of the intravenous formulation of esomeprazole (20 mg and 40 mg) to that of esomeprazole magnesium delayed-release capsules at corresponding doses in patients with symptoms of GERD, with or without erosive esophagitis.
The patients (n=206, 18 to 72 years old; 112 female; 110 Caucasian, 50 Black, 10 Asian, and 36 Other Race) were randomized to receive either 20 mg or 40 mg of intravenous or oral esomeprazole once daily for 10 days (Period 1), and then were switched in Period 2 to the other formulation for 10 days, matching their respective dose level from Period 1.
The intravenous formulation was administered as a 3-minute injection in two of the studies, and as a 15-minute infusion in the other two studies.
Basal acid output (BAO) and maximal acid output (MAO) were determined 22 to 24 hours post-dose on Period 1, Day 11; on Period 2, Day 3; and on Period 2, Day 11.
BAO and MAO were estimated from 1-hour continuous collections of gastric contents prior to and following (respectively) subcutaneous injection of 6 mcg/kg of pentagastrin.
In these studies, after 10 days of once daily administration, the intravenous dosage forms of esomeprazole sodium 20 mg and 40 mg were similar to the corresponding oral dosage forms in their ability to suppress BAO and MAO in these GERD patients (see table below).
There were no major changes in acid suppression when switching between intravenous and oral dosage forms.
Table 5: Mean (SD) BAO and MAO measured 22 to 24 hours post-dose following once daily oral and intravenous administration of esomeprazole for 10 days in GERD patients with or without a history of erosive esophagitis Study Dose in mg Intravenous Administration Method BAO in mmol H+/h MAO in mmol H+/h Intravenous Oral Intravenous Oral 1 (N=42) 20 3-minute injection 0.71 (1.24) 0.69 (1.24) 5.96 (5.41) 5.27 (5.39) 2 (N=44) 20 15-minute infusion 0.78 (1.38) 0.82 (1.34) 5.95 (4) 5.26 (4.12) 3 (N=50) 40 3-minute injection 0.36 (0.61) 0.31 (0.55) 5.06 (3.9) 4.41 (3.11) 4 (N=47) 40 15-minute infusion 0.36 (0.79) 0.22 (0.39) 4.74 (3.65) 3.52 (2.86)
HOW SUPPLIED
16 /STORAGE AND HANDLING Esomeprazole sodium for injection is supplied as a white to off-white, freeze-dried cake containing 20 mg or 40 mg of esomeprazole per single-use vial.
NDC 47335-508-44 one carton containing 10 vials of esomeprazole sodium for injection (each vial contains 20 mg of esomeprazole).
NDC 47335-509-44 one carton containing 10 vials of esomeprazole sodium for injection (each vial contains 40 mg of esomeprazole).
Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [See USP Controlled Room Temperature].
Protect from light.
Store in carton until time of use.
Following reconstitution and administration, discard any unused portion of esomeprazole solution.
RECENT MAJOR CHANGES
Dosage and Administration, Preparation and Administration Instructions ( 2.3 ) 03/2014 Warnings and Precautions, Interactions with Diagnostic Investigations for Neuroendocrine Tumors ( 5.8 ) 03/2014
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients who received oral esomeprazole magnesium in clinical trials, 1,459 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 sodium for injection is supplied as a white to off-white, freeze-dried cake containing 20 mg or 40 mg of esomeprazole per single-use vial.
Esomeprazole sodium for injection is supplied as a freeze-dried cake containing 20 mg or 40 mg of esomeprazole per single-use vial.
( 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 mg to 40 mg and leads to inhibition of gastric acid secretion.
INDICATIONS AND USAGE
1 Esomeprazole sodium for injection is a proton pump inhibitor indicated for the treatment of: Gastroesophageal Reflux Disease (GERD) with erosive esophagitis (EE) in adults and pediatric patients greater than one month of age, when oral therapy is not possible or appropriate.
( 1.1 ) 1.1 Treatment of Gastroesophageal Reflux Disease (GERD) with Erosive Esophagitis Esomeprazole sodium for injection is indicated for the short-term treatment of GERD with erosive esophagitis in adults and pediatric patients 1 month to 17 years, inclusively as an alternative to oral therapy when oral esomeprazole is not possible or appropriate.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of esomeprazole sodium for injection have been established in pediatric patients 1 month to 17 years of age for short-term treatment of GERD with Erosive Esophagitis [ see Clinical Pharmacology, Pharmacokinetics (12.3) ].
However, effectiveness has not been established in patients less than 1 month of age.
1 month to 17 years of age Use of esomeprazole sodium for injection in pediatric patients 1 month to 17 years of age for short-term treatment of GERD with Erosive Esophagitis is supported by: a) results observed from a pharmacokinetic (PK) study on esomeprazole sodium for injection performed in pediatric patients, b) predictions from a population PK model comparing I.V.
PK data between adult and pediatric patients, and c) relationship between exposure and pharmacodynamic results obtained from adult I.V.
and pediatric oral data and d) PK results already included in the current approved labeling and from adequate and well-controlled studies that supported the approval of esomeprazole sodium for injection for adults.
Neonates 0 to 1 month of age Following administration of esomeprazole sodium for injection in neonates the geometric mean (range) for CL was 0.17 L/h/kg (0.04 L/h/kg to 0.32 L/h/kg).
The safety and effectiveness of esomeprazole sodium for injection 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 57 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 Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with esomeprazole sodium for injection 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.
Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 57 times and 35 times, respectively, an oral human dose of 40 mg.
However, 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 33.6 times an oral human dose of 40 mg (see Animal Data) .
Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, esomeprazole sodium for injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 99, 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% 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 Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 57 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times the human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium.
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 57 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 33 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 16.8 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 33.6 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 57 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 33.6 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.
NUSRING MOTHERS
8.3 Nursing Mothers Esomeprazole is likely present in human milk.
Esomeprazole is the S-isomer of omeprazole and limited data indicate that maternal doses of omeprazole 20 mg daily produce low levels in human milk.
Caution should be exercised when esomeprazole sodium for injection is administered to a nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Symptomatic response to therapy with esomeprazole sodium does not preclude the presence of gastric malignancy.
( 5.1 ) Atrophic gastritis has been noted with long-term omeprazole therapy.
( 5.2 ) PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea.
( 5.3 ) Avoid concomitant use of esomeprazole with clopidogrel.
( 5.4 ) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine.
( 5.5 ) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs ( 5.6 ) Avoid concomitant use of esomeprazole sodium with St.
John’s Wort or rifampin due to the potential reduction in esomeprazole levels ( 5.7 , 7.2 ) Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors.
( 5.8 , 12.2 ) 5.1 Risk of Concomitant Gastric Malignancy Symptomatic response to therapy with esomeprazole sodium does not preclude the presence of gastric malignancy.
5.2 Atrophic Gastritis Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer.
5.3 Clostridium difficile Associated Diarrhea Published observational studies suggest that PPI therapy like esomeprazole sodium 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.
5.4 Interaction with Clopidogrel Avoid concomitant use of esomeprazole sodium 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 sodium consider alternative anti-platelet therapy.
[see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] 5.5 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.
The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer).
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.
[ see Dosage and Administration ( 2 ), Adverse Reactions ( 6.2 ) ] 5.6 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy.
Serious adverse events include tetany, arrhythmias, and seizures.
In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
[ See Adverse Reactions ( 6.2 ) ] 5.7 Concomitant use of Esomeprazole Sodium 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 sodium with St.
John’s Wort or rifampin.
5.8 Interactions with 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 )].
5.9 Concomitant use of Esomeprazole Sodium 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 (7.3) ].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to let their healthcare provider know if they are taking, or begin taking other medications, because esomeprazole can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes [ see Drug Interactions (7) ].
Let patients know that antacids may be used while taking esomeprazole sodium for injection.
Advise patients to immediately report and seek care for diarrhea that does not improve.
This may be a sign of Clostridium difficile associated diarrhea [ see Warnings and Precautions (5.3) ].
Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [ see Warnings and Precautions (5.6) ].
Distributed by: Caraco Pharmaceutical Laboratories, Ltd.
1150 Elijah McCoy Drive, Detroit, MI 48202 Manufactured by: Sun Pharmaceutical Ind.
Ltd.
Halol-Baroda Highway, Halol-389 350, Gujarat, India.
ISS.
04/2014 PJPI0275A
DOSAGE AND ADMINISTRATION
2 General Information Esomeprazole sodium for injection should not be administered concomitantly with any other medications through the same intravenous site and/or tubing.
The intravenous line should always be flushed with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of esomeprazole sodium for injection.
The admixture should be stored at room temperature up to 30°C (86°F) and should be administered within the designated time period as listed in Table 1 below.
No refrigeration is required.
Table 1 Storage Time for Final (diluted) Product Diluent Administer within: 0.9% Sodium Chloride Injection, USP 12 hours Lactated Ringer’s Injection, USP 12 hours 5% Dextrose Injection, USP 6 hours Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
As soon as oral therapy is possible or appropriate, intravenous therapy with esomeprazole sodium for injection should be discontinued and the therapy should be continued orally.
GERD – with Erosive Esophagitis ( 2.1 ): Adults: Dose is either 20 mg or 40 mg esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 minutes to 30 minutes).
Pediatric: Give the following doses once daily as an intravenous infusion over 10 minutes to 30 minutes.
( 2.1 ) 1 year to 17 years: Body weight less than 55 kg: 10 mg Body weight 55 kg or greater: 20 mg 1 month to less than 1 year of age: 0.5 mg/kg For patients with severe liver impairment (Child Pugh Class C), a maximum dose of 20 mg once daily of esomeprazole should not be exceeded.
( 2.1 , 8.6 , 12.3 ) 2.1 GERD with Erosive Esophagitis Adult Patients The recommended adult dose is either 20 mg or 40 mg esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 minutes to 30 minutes).
Safety and efficacy of esomeprazole sodium for injection as a treatment of GERD patients with erosive esophagitis for more than 10 days have not been demonstrated.
Dosage adjustment is not required in patients with mild to moderate liver impairment (Child Pugh Classes A and B).
For patients with severe liver impairment (Child Pugh Class C), a maximum dose of 20 mg once daily of esomeprazole sodium for injection should not be exceeded [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology, ( 12.3 )] .
Pediatric Patients The recommended doses for children ages 1 month to 17 years, inclusive, are provided below.
Dose should be infused over 10 minutes to 30 minutes.
1 year to 17 years: Body weight less than 55 kg: 10 mg Body weight 55 kg or greater: 20 mg 1 month to less than 1 year of age: 0.5 mg/kg 2.3 Preparations and Administration Instructions General Information The reconstituted solution of esomeprazole sodium for injection should be stored at room temperature up to 30°C (86°F) and administered within 12 hours after reconstitution.
(Administer within 6 hours if 5% Dextrose Injection is used after reconstitution).
No refrigeration is required [see Dosage and Administration ( 2 ), Table 1 ].
Gastroesophageal Reflux Disease (GERD) with Erosive Esophagitis Preparation Instructions for Adult Patients Intravenous Injection (20 mg or 40 mg vial) over no less than 3 minutes The freeze-dried powder should be reconstituted with 5 mL of 0.9% Sodium Chloride Injection, USP.
Withdraw 5 mL of the reconstituted solution and administer as an intravenous injection over no less than 3 minutes.
Preparation Instructions for Pediatric Patients Intravenous Infusion (20 mg or 40 mg) over 10 minutes to 30 minutes A solution for intravenous infusion is prepared by first reconstituting the contents of one vial * with 5 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP and further diluting the resulting solution to a final volume of 50 mL.
The resultant concentration after diluting to a final volume of 50 mL is 0.8 mg/mL (for 40 mg vial) and 0.4 mg/mL (for 20 mg vial).
The solution (admixture) should be administered as an intravenous infusion over a period of 10 minutes to 30 minutes.
*For patients 1 month to less than 1 year of age, first calculate the dose (0.5 mg/kg) to determine the vial size needed.