"Overview of Heartburn
The esophagus is a tube that connects the mouth to the stomach. It is made of muscles that work to push food toward the stomach in rhythmic waves. Once in the stomach, food is prevented from refluxing (moving b"...
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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.
The effect of intravenous esomeprazole on intragastric pH was determined in two separate studies. In the first study, 20 mg of NEXIUM I.V. for Injection was administered intravenously once daily at constant rate over 30 minutes for 5 days. Twenty-two healthy subjects were included in the study. In the second study, 40 mg of NEXIUM I.V. for Injection was administered intravenously once daily at constant rate over 30 minutes for 5 days. Thirty-eight healthy subjects were included in the study.
Table 3 : Effect of NEXIUM I.V. for Injection on
Intragastric pH on Day 5
|Esomeprazole 20 mg (n=22)||Esomeprazole 40 mg (n=38)|
|% Time Gastric pH > 4||49.5||66.2|
|Gastric pH was measured over a 24-hour period|
Serum Gastrin Effects
In oral studies, the effect of NEXIUM on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors.
Enterochromaffin-like (ECL) Cell Effects
There are no data available on the effects of intravenous esomeprazole on ECL cells.
In 24-month carcinogenicity studies of oral omeprazole in rats, a dose-related significant occurrence of gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Nonclinical Toxicology]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.
Human gastric biopsy specimens have been obtained from more than 3,000 patients treated orally with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.
In over 1,000 patients treated with NEXIUM (10, 20 or 40 mg/day) up to 6-12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.
NEXIUM had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of NEXIUM on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.
The pharmacokinetic profile of NEXIUM I.V. for Injection 20 mg and 40 mg was determined in 24 healthy volunteers for the 20 mg dose and 38 healthy volunteers for the 40 mg dose following once daily administration of 20 mg and 40 mg of NEXIUM I.V. for Injection by constant rate over 30 minutes for five days. The results are shown in the following table:
Table 4 : Pharmacokinetic Parameters of NEXIUM Following
I.V. Dosing for 5 days
|Parameter||NEXIUM I.V. 20 mg||NEXIUM I.V. 40 mg|
|AUC(μmol*h/L)||5.11 (3.96:6.61)||16.21 (14.46:18.16)|
|Cmax (μmol/L)||3.86 (3.16:4.72)||7.51 (6.93:8.13)|
|t½ (h)||1.05 (0.90:1.22)||1.41 (1.30:1.52)|
|Values represent the geometric mean (95% CI)|
Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 220 μmol/L. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L.
Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole's metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15-20% of Asians lack CYP2C19 and are termed Poor Metabolizers. At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive metabolizers) is approximately 2.
Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer.
Esomeprazole is excreted as metabolites primarily in urine but also in feces. Less than 1% of parent drug is excreted in the urine. Esomeprazole is completely eliminated from plasma, and there is no accumulation during once daily administration. The plasma elimination half-life of intravenous esomeprazole is approximately 1.1 to 1.4 hours and is prolonged with increasing dose of intravenous esomeprazole.
Investigation of age, gender, race, renal, and hepatic impairment and metabolizer status has been made previously with oral esomeprazole. The pharmacokinetics of esomeprazole is not expected to be affected differently by intrinsic or extrinsic factors after intravenous administration compared to oral administration. The same recommendations for dose adjustment in special populations are suggested for intravenous esomeprazole as for oral esomeprazole.
In oral studies, the AUC and Cmax values were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment based on age is not necessary.
In a randomized, open-label, multi-national, repeated dose study, esomeprazole PK was evaluated following a once-daily 3-minute injection in a total of 50 pediatric patients 0 to 17 years old, inclusive. Esomeprazole plasma AUC values for 20 mg NEXIUM IV were 183% and 60% higher in pediatric patients aged 6 – 11 years and 12 –17 years respectively compared to adults given 20 mg. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 0.5 mg/kg once-daily for pediatric patients 1-11 months of age, 10 mg for pediatric patients 1-17 years with body weight < 55 kg, and 20 mg for pediatric patients 1-17 years with body > 55 kg would achieve comparable steady-state plasma exposures (AUC0-24) to those observed in adult patients administered 20 mg of NEXIUM I.V. once every 24 hours. Further, increasing the infusion duration from 3 minutes to 10 minutes or 30 minutes was predicted to produce steady-state Cmax values that were comparable to those observed in adult patients at the 40 mg and 20 mg NEXIUM I.V. doses.
In oral studies, the AUC and Cmax values were slightly higher (13%) in females than in males at steady state. Similar differences have been seen for intravenous administration of esomeprazole. Dosage adjustment based on gender is not necessary.
In oral studies, the steady state pharmacokinetics of esomeprazole obtained after administration of 40 mg once daily to 4 patients each with mild (Child Pugh Class A), moderate (Child Pugh Class B), and severe (Child Pugh Class C) liver insufficiency were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic insufficiency, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic insufficiency the AUCs were 2 to 3 times higher than in the patients with normal liver function. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child Pugh Class C) a dose of 20 mg once daily should not be exceeded [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
The pharmacokinetics of esomeprazole in patients with renal impairment are not expected to be altered relative to healthy volunteers as less than 1% of esomeprazole is excreted unchanged in urine.
Effects on Gastrointestinal Microbial Ecology
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile.
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 NEXIUM 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 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 22-24 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 6.0 mcg/kg of pentagastrin.
In these studies, after 10 days of once daily administration, the intravenous dosage forms of NEXIUM 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 22-24 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
|Study||Dose in mg||Intravenous Administration Method||BAO in mmol H+/h||MAO in mmol H+/h|
|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 (4.00)||5.26 (4.12)|
|3 (N=50)||40||3-minute injection||0.36 (0.61)||0.31 (0.55)||5.06 (3.90)||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)|
Last reviewed on RxList: 2/3/2012
This monograph has been modified to include the generic and brand name in many instances.
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