1 Name of Medicine
Esomeprazole AN contains esomeprazole sodium.
2 Qualitative and Quantitative Composition
Esomeprazole sodium is a white to yellowish white solid.
Esomeprazole is a proton pump inhibitor and is a substituted benzimidazole. Esomeprazole is the S-isomer of omeprazole. It is optically stable in vivo, with negligible conversion to the R-isomer.
Esomeprazole AN is available as a white or almost white lyophilized powder for injection.
Each vial contains esomeprazole sodium 42.5 mg, equivalent to 40 mg esomeprazole, disodium edetate 1.0 mg and sodium hydroxide q.s. for pH adjustment.
3 Pharmaceutical Form
See Section 2 Qualitative and Quantitative Composition.
4 Clinical Particulars
4.9 Overdose
The symptoms described in connection with deliberate esomeprazole overdose (limited experience of oral doses in excess of 240 mg/day) are transient. Single oral doses of 80 mg and intravenous doses of 100 mg esomeprazole were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.
Reports of overdosage with omeprazole in humans may also be relevant. In the literature doses of up to 560 mg have been described and occasional reports have been received when single oral doses have reached up to 2400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported from overdosage with omeprazole. Also apathy, depression and confusion have been described in single cases. The symptoms described in connection to omeprazole overdosage have been transient, and no serious clinical outcome due to omeprazole has been reported. The rate of elimination was unchanged (first-order kinetics) with increased doses and no specific treatment has been needed.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Preclinical bridging studies between the enantiomer esomeprazole and the racemate (omeprazole) showed that these compounds are pharmacologically and toxicologically similar at equivalent systemic exposure. Thus, the extensive preclinical database for omeprazole is also relevant for the safety assessment of esomeprazole.
Preclinical studies on esomeprazole reveal no particular hazard for humans, based on conventional studies of single and repeated dose toxicity, embryo-foetal toxicity and mutagenicity. As in the oral studies, repeated intravenous administration of esomeprazole to animals resulted in few and primarily mild effects. However, very high intravenous doses caused an acute toxic response that consisted of occasional, nonspecific and short-lived CNS signs. This effect appeared to be associated with the Cmax rather than the AUC of esomeprazole. Comparison of the Cmax values in humans given 40 mg as a 3-minute injection or 80 mg as a 30 minute infusion and the plasma concentrations that were acutely toxic in animals showed a wide margin of safety (at least 6-fold for total and 20-fold for unbound plasma concentrations).
Genotoxicity. Esomeprazole was negative in a bacterial gene mutation assay. In clastogenicity tests, esomeprazole was positive (as was omeprazole) in an in vitro chromosome aberration test in human lymphocytes. However, three oral in vivo tests (an oral mouse micronucleus test, an oral chromosome aberration test in rat bone marrow and an intravenous chromosomal aberration test in mouse bone marrow) in the presence of long and high systemic exposure to esomeprazole, showed that esomeprazole was not clastogenic under in vivo conditions. Exposure levels in man are well below those at which clastogenic effects occurred in vitro.
Carcinogenicity. No carcinogenicity studies have been conducted on esomeprazole. However, long-term treatment with omeprazole (the racemate) produced enterochromaffin-like (ECL) cell hyperplasia and gastric carcinoids in rats. In a 104-week study in rats, carcinoids were observed at doses (on a mg/m2 basis), which ranged from 0.4 to 30-fold the maximum clinical dose of esomeprazole. A no-effect dose level was not determined in female rats. A similar effect was not observed in a 78-week mouse carcinogenicity study with omeprazole, nor in a 26-week study in wild type and heterozygous p53+/- knockout mice (at a maximum tolerated dose that was 90-fold the maximum clinical dose, on a mg/m2 basis), although gastric cell hyperplasia occurred. These gastric effects in the rat are believed to be the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid. Similar effects are elicited by other proton pump inhibitors, H2-receptor antagonists and by partial fundectomy.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Chemical structure. The chemical name is (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole sodium. The chemical structure of esomeprazole sodium is:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSESOSOD.gif Molecular formula: C17H18N3O3SNa.
Molecular weight: 367.4.
CAS number. 161796-78-7.
7 Medicine Schedule (Poisons Standard)
Schedule 4 (Prescription Only Medicine).
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/ESOINJST.gif
