Esomeprazole Sodium 40 mg · Dry-powder injectables

Esomeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

Absorption — The pharmacokinetics of esomeprazole in healthy subjects following administration of esomeprazole sodium for injection 20 mg and 40 mg once daily as intravenous infusion over 30 minutes for 5 days are shown in Table 8.

Following intravenous administration of esomeprazole sodium for injection in 24 healthy subjects as a loading dose of 80 mg over 30 minutes followed by a continuous infusion of 8 mg/hour for 23.5 hours (for a total of 24 hours), esomeprazole pharmacokinetic parameters [geometric mean value (95% CI)] were as follows: AUC t111.1 micromol*h/L (100.5, 122.7 micromol*h/L), C max15.0 micromol/L (13.5, 16.6 micromol/L), and steady state plasma concentration (C ss) 3.9 micromol/L (3.5, 4.5 micromol/L). In another study of healthy Caucasian subjects administered the same treatment regimen.

Esomeprazole is a time-dependent inhibitor of CYP2C19, resulting in autoinhibition and nonlinear pharmacokinetics. The systemic exposure increases in a more than dose proportional manner after multiple oral doses of esomeprazole. Compared to the first dose, the systemic exposure (C maxand AUC 0-24h) at steady state following once a day dosing increased by 43% and 90%, respectively, compared to after the first dose for the 20 mg dose and increased by 95% and 159%, respectively, for the 40 mg dose.

Distribution — Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 micromol/L. The apparent volume of distribution at steady state in healthy subjects 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.

Excretion — 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 esomeprazole following intravenous administration of esomeprazole sodium for injection is approximately 1.1 to 1.4 hours and is prolonged with increasing doses.

The plasma clearance (CL) is approximately 5.9 to 7.2 L/h during administration of esomeprazole sodium for injection as an intravenous infusion of 80 mg over 30 minutes followed by a continuous infusion of 8 mg/hour for 23.5 hours.

Geriatric Patients — The AUC and C maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. This increase in exposure is not considered clinically relevant.

Pediatric Patients — The pharmacokinetics of esomeprazole were evaluated in 50 pediatric patients birth to 17 years of age, inclusive (of which 44 pediatric patients were 1 month to 17 years) in a randomized, open-label, multi-national, multiple dose study of 20 mg esomeprazole sodium for injection administered as a once-daily 3-minute intravenous injection. Esomeprazole plasma AUC values were 183% and 60% higher in pediatric patients aged 6 to 11 years and 12 to 17 years, respectively, compared to adults.

Subsequent pharmacokinetic analyses predicted the following dosage regimens would achieve comparable steady-state plasma exposures (AUC 0-24) to those observed in adult patients administered 20 mg of esomeprazole sodium for injection once daily: 0.5 mg/kg once daily for pediatric patients 1 month to 11 months of age, 10 mg once daily for pediatric patients 1 year to 17 years with body weight less than 55 kg, and 20 mg once daily for pediatric patients 1 year to 17 years with body weight of 55 kg and greater. Increasing the infusion duration from 3 minutes to 10 minutes or 30 minutes was predicted to produce steady-state C maxvalues that were comparable to those observed in adult patients at the 40 mg and 20 mg esomeprazole sodium for injection doses, respectively [see Use in Specific Populations (8.4)] .