Prescription Drug Information: Esomeprazole Strontium (Page 4 of 8)

8.4 Pediatric Use

The safety and effectiveness of esomeprazole strontium delayed-release capsules have not been established in pediatric patients. Strontium is known to compete with calcium for intestinal absorption and is incorporated into bone. Therefore, use in pediatric patients is not recommended because adequate safety studies have not been performed.

In a juvenile rat toxicity study, following administration of either esomeprazole strontium or esomeprazole magnesium at equimolar oral doses of 140 to 280 mg esomeprazole/kg/day (34 to 57 times the daily MRHD of 40 mg on a body surface area basis), increases in deaths were seen at the high dose, along with treatment-related decreases in body weight and body weight gain, decreases in femur weight and femur length and decreases in overall growth [see Nonclinical Toxicology (13.2)].

Symptomatic GERD in infants less than one year of age

A pediatric study of esomeprazole magnesium did not establish efficacy for symptomatic GERD in patients less than 1 year of age. A multicenter, randomized, double-blind, placebo-controlled, treatment-withdrawal study of 98 patients ages 1 to 11 months, inclusive, with symptomatic GERD did not demonstrate a difference between esomeprazole magnesium and placebo.

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.

8.6 Use in Patients with Renal Impairment

No dosage adjustment is necessary in patients with mild to moderate renal impairment. The pharmacokinetics and safety of strontium in patients with severe renal impairment has not been studied and, therefore, use in this patient population is not recommended.

10 OVERDOSAGE

A single oral dose of esomeprazole at 510 mg/kg (about 103 times the human dose on a body surface area basis), was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions.

The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg of esomeprazole were uneventful. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert — Adverse Reactions). No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive.

As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose contact a Poison Control Center at 1-800-222-1222.

11 DESCRIPTION

The active ingredient in the proton pump inhibitor esomeprazole strontium delayed-release capsules is bis(5‑ methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H -benzimidazole-1-yl) strontium tetrahydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. The molecular formula of esomeprazole strontium is (C17 H18 N3 O3 S)2 ·Sr·4H2 O with molecular weight of 848.50. The structural formula is:

Figure 1

Structural Formula
(click image for full-size original)

The strontium salt is a white or almost white crystalline powder. Each molecule contains 4 moles of water of solvation and is soluble in water.

Esomeprazole strontium is supplied in delayed-release capsules. Each delayed-release capsule contains 24.65 mg esomeprazole strontium equivalent to 20 mg esomeprazole or 49.3 mg esomeprazole strontium equivalent to 40 mg esomeprazole, in the form of enteric-coated granules with the following inactive ingredients: calcium carbonate, hypromellose, methacrylic acid copolymer dispersion, mono- and diglycerides, polysorbate 80, sugar spheres, talc, triethyl citrate. The 24.65 mg capsule shells have the following inactive ingredients: gelatin, titanium dioxide, synthetic iron oxide. The 49.3 mg capsule shells have the following inactive ingredients: gelatin, titanium dioxide, FD&C Blue #1, FD&C Red #40, FD&C Yellow #6.

Each 24.65 mg capsule contains 2.6 mg of strontium. Each 49.3 mg capsule contains 5.1 mg of strontium.

12 CLINICAL PHARMACOLOGY

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.

12.2 Pharmacodynamics

Antisecretory Activity

The effect of esomeprazole magnesium on intragastric pH was determined in patients with symptomatic gastroesophageal reflux disease in two separate studies. In the first study of 36 patients, 44.6 mg of esomeprazole magnesium (equivalent to 40 mg of esomeprazole) and 22.3 mg of esomeprazole magnesium (equivalent to 20 mg of esomeprazole) were administered over 5 days. The results are shown in Table 3:

Table 3: Effect on Intragastric pH on Day 5 (N=36)

Parameter

esomeprazole magnesium 44.6 mg

esomeprazole magnesium 22.3 mg

% Time Gastric pH >4 (Hours)

70%* (16.8 h)

53% (12.7 h)

Coefficient of variation

26%

37%

Median 24 Hour pH

4.9*

4.1

Coefficient of variation

16%

27%

Gastric pH was measured over a 24-hour period.

* p< 0.01 esomeprazole magnesium 44.6 mg vs. esomeprazole magnesium 22.3 mg

In a second study, the effect on intragastric pH of esomeprazole magnesium 44.6 mg administered once daily over a five-day period was similar to the first study, (% time with pH >4 was 68% or 16.3 hours).

Serum Gastrin Effects

The effect of esomeprazole magnesium 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 to 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

In 24-month carcinogenicity studies of 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 (13.1) ]. 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 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 esomeprazole magnesium (10, 20, or 40 mg/day) up to 6 to 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.

Endocrine Effects

Esomeprazole magnesium had no effect on thyroid function when given in oral doses of 22.3 mg or 44.6 mg for 4 weeks. Other effects of esomeprazole 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.

12.3 Pharmacokinetics

Absorption

Following single oral administration of esomeprazole strontium delayed-release capsules 49.3 mg (equivalent to 40 mg of esomeprazole) in 36 healthy adults under fasting conditions, the peak plasma concentrations (Cmax) of esomeprazole occurred at approximately 1.7 hours post-dose. Mean esomeprazole Cmax and area under the plasma concentration‑time curve (AUC) were comparable to those for esomeprazole magnesium delayed-release capsules 44.6 mg (equivalent to 40 mg of esomeprazole). In a study using esomeprazole magnesium delayed-release capsules, esomeprazole Cmax increased proportionally when the dose was increased, and there was a three‑fold increase in esomeprazole AUC when the dose was increased from 22.3 mg (equivalent to 20 mg of esomeprazole) to 44.6 mg. Systemic bioavailability will increase following multiple dosing and esomeprazole AUC is expected to increase to approximately 2.6‑fold after once daily dosing of esomeprazole strontium delayed-release capsules 49.3 mg for 5 days.

In one single dose study in 39 healthy adult subjects under fasting conditions, the capsule contents of esomeprazole strontium delayed-release capsules 49.3 mg were sprinkled onto one tablespoon of applesauce, mean esomeprazole Cmax and AUC were comparable to those for esomeprazole magnesium delayed-release capsules 44.6 mg administered under the same conditions. In a food-effect study, the AUC after administration of a single 49.3 mg dose of esomeprazole strontium delayed-release capsules decreased by 52% after a high fat meal compared to fasting conditions. Esomeprazole strontium delayed-release capsules should be taken at least one hour before meals.

Table 4: Pharmacokinetic Parameters of Esomeprazole Following Single Oral Administration in Healthy Adult Volunteers under Fasting Conditions

Parameters

Esomeprazole strontium delayed-release capsules 49.3 mg

Esomeprazole strontium delayed-release capsules 49.3 mg (with one tablespoon of apple saucea)

Meanb

SD

Meanb

SD

Cmax (ng/mL)

1105.6

464.8

1155.6

429.8

Tmax (h)

1.7

2.3

AUC0-tlast (ng*h/Ml)

2283.9

1400.4

2389.1

1071.4

AUC0-∞ (ng*h/mL)

2310.9

1428.3

2417.8

1081.8

a Capsule contents were administered with one tablespoon of applesauce under otherwise fasting conditions.
b Values represent the arithmetic mean, except Tmax , which is the median.

Distribution

Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 μmol/L. The apparent volume of distribution at steady-state in healthy volunteers is approximately 16 L.

Metabolism

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 to 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.

Excretion

The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.

Combination Therapy with Antimicrobials

Esomeprazole magnesium 44.6 mg once daily was given in combination with clarithromycin 500 mg twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady-state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively, during triple combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during coadministration with clarithromycin and amoxicillin is not expected to produce significant safety concerns.

The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple combination therapy and administration of each drug alone. However, the mean AUC and Cmax for 14-hydroxyclarithromycin increased by 19% and 22%, respectively, during triple combination therapy compared to treatment with clarithromycin alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically significant.

Concomitant Use with Clopidogrel

Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole magnesium 44.6 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite.

Special Populations

Geriatric

The esomeprazole AUC and Cmax values were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects after administration of esomeprazole magnesium to steady state. Dosage adjustment based on age is not necessary.

Gender

The esomeprazole AUC and Cmax values were slightly higher (13%) in females than in males after administration of esomeprazole magnesium to steady state. Dosage adjustment based on gender is not necessary.

Hepatic Insufficiency

The steady state pharmacokinetics of esomeprazole obtained after administration of esomeprazole magnesium 44.6 mg once daily to 4 patients each with mild (Child Pugh 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 esomeprazole 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) esomeprazole strontium dose of 24.65 mg once daily should not be exceeded [see Dosage and Administration (2) ].

Renal Insufficiency

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. In a study with a different strontium product and dose in patients with mild to moderate renal impairment, strontium clearance was reduced with the decrease in creatinine clearance. The pharmacokinetics of strontium in patients with severe renal impairment has not been characterized [see Use in Specific Populations (8.6) ].

Other pharmacokinetic observations

Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole.

Studies evaluating concomitant administration of esomeprazole magnesium 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.

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