Esomeprazole Strontium (Page 4 of 10)

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 (5.9) ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well controlled studies of esomeprazole strontium delayed-release capsules in pregnant women. Teratogenicity was not observed in an embryofetal developmental study in rats with either esomeprazole strontium or esomeprazole magnesium at equimolar oral doses up to 280 mg esomeprazole/kg/day (about 57 times the daily maximum recommended human dose (MRHD) of 40 mg on a body surface area basis). When administered as either the strontium or magnesium salt, changes in bone morphology and physeal dysplasia were observed in pre- and postnatal developmental toxicity studies in rats at doses equal to or greater than 138 mg esomeprazole/kg/day (approximately 33.6 times the daily MRHD of 40 mg on a body surface area basis). Because of the observed effect at the high doses of esomeprazole strontium on developing bone in rat studies, esomeprazole strontium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

An embryofetal developmental (teratogenicity) study in rats was performed with both esomeprazole strontium and esomeprazole magnesium at equimolar oral doses of 14 to 280 mg esomeprazole/kg/day (about 3.4 to 57 times the daily maximum recommended human dose (MRHD) of 40 mg, on a body surface area basis). At the doses tested, there were no teratogenic or adverse effects on general fetal development or on fetal visceral or skeletal structures. In addition, there was no adverse effect on maternal and fetal bone calcium levels when esomeprazole was administered as either the strontium or magnesium salt. Fetal exposure to strontium and esomeprazole was dose-related.

Pre- and postnatal developmental toxicity studies in rats with additional endpoints to evaluate bone development were performed with both esomeprazole strontium and esomeprazole magnesium at equimolar oral doses of 14 to 280 mg esomeprazole/kg/day (about 3.4 to 57 times the daily MRHD of 40 mg of esomeprazole on a body surface area basis). The rats were fed either a standard diet or a diet with reduced levels of calcium and Vitamin D. When administered as either the strontium or magnesium salt, neonatal/early postnatal (birth to weaning) survival was decreased, 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 esomeprazole/kg/day (about 16.8 times the daily MRHD of 40 mg on a body surface area basis). In addition, when administered as either the strontium or magnesium salt, 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 esomeprazole/kg/day (about 3.4 times the MRHD 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 (as either the strontium or the magnesium salt) at doses equal to or greater than 138 mg/kg/day (about 33.6 times the daily MRHD of 40 mg on a body surface area basis). No significant differences were observed between the groups fed nutritionally complete diet and those fed the diet with reduced levels of calcium and Vitamin D.

Adverse effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity studies when esomeprazole strontium or esomeprazole magnesium were administered at equimolar oral doses of 14 to 280 mg esomeprazole/kg/day (about 3.4 to 57 times the daily MRHD 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 esomeprazole/kg/day (about 33.6 times the daily MRHD of 40 mg on a body surface area basis).

8.3 Nursing Mothers

Limited published data indicate that esomeprazole and strontium are present in human milk. Because of the effect of esomeprazole strontium observed at high doses on developing bone in rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.1)].

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

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.