Drugs

, Volume 62, Issue 10, pp 1503–1538

Esomeprazole

A Review of its Use in the Management of Acid-Related Disorders
  • Lesley J. Scott
  • Christopher J. Dunn
  • Gordon Mallarkey
  • Miriam Sharpe
Adis Drug Evaluation
  • 223 Downloads

Summary

Abstract

Esomeprazole (S-isomer of omeprazole), the first single optical isomer proton pump inhibitor, generally provides better acid control than current racemic proton pump inhibitors and has a favourable pharmacokinetic profile relative to omeprazole.

In a large well designed 8-week trial in patients (n >5000) with erosive oesophagitis, esomeprazole recipients achieved significantly higher rates of endoscopically confirmed healed oesophagitis than those receiving lansoprazole. Respective healed oesophagitis rates with once-daily esomeprazole 40mg or lansoprazole 30mg were 92.6 and 88.8%. Overall, esomeprazole was also better than omeprazole, although these differences were not always statistically significance. Ninety-two to 94% of esomeprazole recipients (40mg once daily) achieved healed oesophagitis versus 84 to 90% of omeprazole recipients (20mg once daily). Esomeprazole was effective across all baseline grades of oesophagitis; notably, relative to lansoprazole, as baseline severity of disease increased, the difference in rates of healed oesophagitis also increased in favour of esomeprazole. Resolution of heartburn was also significantly better with esomeprazole 40mg than with these racemic proton pump inhibitors. Long-term (up to 12 months) therapy with esomeprazole effectively maintained healing in these patients.

Once-daily esomeprazole 20 or 40mg for 4 weeks resolved symptoms in patients with symptomatic gastro-oesophageal reflux disease (GORD) without oesophagitis. Symptoms were effectively managed in the long-term with symptom-driven on-demand esomeprazole (20 or 40mg once daily).

Eradicating Helicobacter pylori infection is considered pivotal to successfully managing duodenal ulcer disease. Seven days’ treatment (twice-daily esomeprazole 20mg plus amoxicillin 1g and clarithromycin 500mg) eradicated H. pylori in ≥86% of patients (intention-to-treat), a rate that was similar to equivalent omeprazole-based regimens.

Esomeprazole is generally well tolerated, both as monotherapy and in combination with antimicrobial agents, with a tolerability profile similar to that of other proton pump inhibitors. Few patients discontinued therapy because of treatment-emergent adverse events (<3% of patients), with very few (<1%) drug-related serious adverse events reported.

Conclusions: Esomeprazole is an effective, well tolerated treatment for managing GORD and for eradicating H. pylori infection in patients with duodenal ulcer disease. In 8-week double-blind trials, esomeprazole healed oesophagitis and resolved symptoms in patients with endoscopically confirmed erosive oesophagitis and overall, provided better efficacy than omeprazole. Notably, in a large (n >5000 patients) double-blind trial, esomeprazole 40mg provided significantly better efficacy than lansoprazole in terms of healing rates and resolution of symptoms. Long-term therapy with esomeprazole maintained healed oesophagitis in these patients. Esomeprazole also proved beneficial in patients with symptomatic GORD without oesophagitis. Thus, esomeprazole has emerged as an option for first-line therapy in the management of acid-related disorders.

Pharmacodynamic Properties

Esomeprazole inhibits the activity of the H+/K+-ATPase enzyme (the proton pump), and thereby reduces secretion of hydrochloric acid by gastric parietal cells.

Superiority of esomeprazole 40mg daily over omeprazole, lansoprazole, rabeprazole and pantoprazole in terms of elevation of intragastric pH has been shown in a number of randomised, crossover trials (most of which were nonblind) in healthy volunteers and patients with symptoms of gastro-oesophageal reflux disease (GORD). On the fifth day of treatment intragastric pH was >4 for a mean 59.4 to 69.8% of the monitored 24-hour periods in individuals receiving esomeprazole 40mg daily. These percentages were significantly greater than those with comparators (43.7 to 62% for esomeprazole 20mg, omeprazole 20 or 40mg, rabeprazole 20mg, pantoprazole 40mg, lansoprazole 30mg daily). Similarly, esomeprazole 20mg daily was superior to omeprazole 20mg or lansoprazole 15mg daily in the maintenance of intragastric pH >4. Higher percentages of patients receiving esomeprazole 20 or 40mg compared with recipients of other agents maintained intragastric pH >4 for periods ranging from at least 8 hours to more than 16 hours. In one nonblind study in 35 patients with GORD receiving esomeprazole 40mg or rabeprazole 20mg daily, pH was >4 for 23.2 and 11%, respectively, of the first 4 hours after administration of the first dose of study medication, indicating a more rapid onset of reduction of intragastric pH with esomeprazole.

Esomeprazole has no apparent effect on a variety of endocrine and metabolic functions, but the drug increases fasting serum gastrin levels in a dose-related fashion.

Pharmacokinetic Profile

Esomeprazole is absorbed rapidly after oral administration, with areas under the plasma concentration-time curves (AUCs) increasing in a nonlinear dose-related fashion after single doses. Systemic exposure to esomeprazole [as shown by mean AUC extrapolated to infinity (AUC)] increases with repeated administration of the drug (by 90% with 20mg daily and 159% with 40mg daily relative to day 1 after 5 day’s treatment in healthy volunteers). This effect is attributed to reductions n total body clearance and first-pass metabolism with repeated doses. Binding to plasma proteins of esomeprazole (97%) is similar to that seen with omeprazole and other proton pump inhibitors.

Metabolism of esomeprazole is via hepatic cytochrome P450 (CYP) isoenzymes, chiefly CYP3A4 and CYP2C19, with approximately 80% of each dose being excreted as metabolites in the urine. A small proportion of the population lacks a functional form of the CYP2C19 isoenzyme and are therefore poor metabolisers of esomeprazole. AUC data indicate that dosage adjustments are not necessary in these individuals.

Comparative pharmacokinetic data obtained in patients with GORD show similar times to attainment of peak plasma concentrations with esomeprazole and omeprazole (approximately 1 hour). However, after 5 days’ treatment, the geometric mean AUC for esomeprazole 20mg was approximately two times higher than that for omeprazole 20mg daily, whereas that for esomeprazole 40mg daily was over five times higher than omeprazole 20mg (p < 0.0001 for both differences) in a study in 36 evaluable patients. There was also less interpatient variability in AUC values with esomeprazole than with omeprazole, although statistical significance was not stated for this finding.

Systemic exposure to esomeprazole is not increased sufficiently to warrant tolerability concerns in patients with mild to moderate hepatic insufficiency; maximum plasma concentrations increased 28% in 12 patients with mild (Child-Pugh class A) to severe (Child-Pugh class C) hepatic insufficiency. There are no clinically significant gender effects on the drug’s disposition. The potential for interactions between esomeprazole and other drugs is reported to be low and similar to that with omeprazole.

Clinical Efficacy

In patients with erosive GORD: In randomised, double-blind, multicentre trials of 8 weeks’ duration (the usual duration of these trials), esomeprazole effectively healed oesophagitis (primary efficacy endpoint) and resolved heartburn (secondary endpoint) in patients with GORD. Patients received oral esomeprazole 20 or 40mg, lansoprazole 30mg or omeprazole 20mg once daily before breakfast. Patients who showed endoscopically confirmed healed oesophagitis were discontinued from studies at 4 weeks.

Overall, esomeprazole was better than omeprazole in terms of endoscopically confirmed healed oesophagitis and resolution of symptoms, although these differences favouring esomeprazole were not always statistically significant. Notably, in a large (n >5000 patients) well designed trial, significantly more recipients of esomeprazole 40mg once daily than lansoprazole 30mg once daily showed healed oesophagitis at 8 weeks (92.6 vs 88.8% of patients; p < 0.001). Similarly, 92 to 94% of esomeprazole (40mg once daily) recipients achieved healed oesophagitis at 8 weeks compared with 84 to 90% of those receiving omeprazole 20mg daily. Of these double-blind trials, one evaluated both esomeprazole 20mg and 40mg; a significantly higher percentage of patients achieved healed oesophagitis in both the esomeprazole 20 (89.9% of patients; p < 0.05 vs omeprazole) and 40mg (94.1%; p < 0.001 vs omeprazole) groups than in the omeprazole 20mg group (86.9%). Evidence-based analysis using pooled data from two trials confirmed that esomeprazole was more effective than omeprazole in healing erosive oesophagitis; 11 patients would need to be treated with esomeprazole 40mg once daily rather than omeprazole 20mg once daily to prevent one treatment failure.

The higher response rates with esomeprazole treatment relative to omeprazole occurred across all baseline grades of disease severity (based on Los Angeles Classification grades). Furthermore, relative to lansoprazole, as the baseline severity of disease increased, the difference in rates of healed oesophagitis also increased in favour of esomeprazole.

Esomeprazole also proved effective in patients with erosive oesophagitis according to secondary efficacy endpoints (e.g. percentage of heartburn-free days and nights, and the time to sustained resolution of symptoms). Heartburn resolution with esomeprazole 40mg was significantly better than that of omeprazole for all secondary efficacy endpoints, with a significantly reduced time to complete resolution of symptoms. Furthermore, esomeprazole recipients experienced significantly more nights without heartburn relative to lansoprazole, (87.1 vs 85.8% of nights heartburn-free; p ≤0.05), with complete resolution of symptoms occurring sooner in the esomeprazole group (7 vs 8 days; p ≤0.01); there was no between-group difference in the number of days without heartburn.

Resolution of symptoms matched healed oesophagitis rates in a post-hoc analysis of pooled data from 8-week randomised, double-blind trials evaluating 4877 patients. After 4 weeks’ treatment with esomeprazole 40mg once daily, 83.4 and 81% of recipients who had healed oesophagitis were asymptomatic for heartburn and acid regurgitation, respectively, compared with 75.4 and 71.6% of those receiving omeprazole 20mg once daily (p < 0.001 for both comparisons).

Maintenance therapy in patients with GORD: Esomeprazole 20 or 40mg once daily was significantly more effective than placebo in maintaining healing, prolonging the time to recurrence of erosive oesophagitis in two 6-month randomised, double-blind, multicentre trials. Healed oesophagitis was maintained in 79 and 93% (esomeprazole 20mg), 88 and 94% (esomeprazole 40mg), or 29% (placebo) of patients. Subgroup analyses indicated that maintenance of healing with esomeprazole treatment was not influenced by gender, age (≥65 years vs <65 years of age), initial treatment during the healing phase, time to healing in this phase (4 vs 8 weeks) or baseline severity of erosive oesophagitis. Similar results were reported in a noncomparative trial of 12 months’ duration.

Although there was no statistically significant difference in the percentage of patients who were heartburn-free at 6 months with esomeprazole and placebo treatment, this most likely reflects the fact that only patients with maintained healing remained in the study at 6 months.

A significantly higher percentage of esomeprazole (20mg once daily) than lansoprazole (15mg once daily) recipients remained in remission (primary end-point) at 6 months in a large, randomised, double-blind trial (83 vs 74% of patients; p < 0.001). Esomeprazole recipients showed higher rates of remission across all grades of baseline disease severity than lansoprazole-treated patients. Furthermore, significantly more esomeprazole than lansoprazole recipients were asymptomatic at 6 months [heartburn-free (78 vs 71% of patients), acid regurgitation-free (81 vs 72%) and epigastric pain-free (80 vs 75%)].

In patients with symptomatic GORD without oesophagitis: Esomeprazole 20 or 40mg once daily for 4 weeks effectively resolved symptoms in patients with symptomatic GORD without oesophagitis in two randomised double-blind trials. Thirty-three to 42% of patients achieved complete resolution of heartburn (no heartburn during the final 7 days of the 4-week studies) with esomeprazole versus 12 and 14% of placebo recipients. Additionally, 63 to 68% of days were heartburn-free with esomeprazole (20 or 40mg once daily) therapy compared with 36 and 46% with placebo. Respective median times to sustained resolution of heartburn were also significantly shorter in patients receiving esomeprazole (12.1 to 17.3 vs 20.8 and 22.3 days).

Symptom-driven on-demand therapy (esomeprazole 20 or 40mg once daily) was effective in the management of patients with symptomatic GORD without erosive oesophagitis in two 6-month randomised, double-blind, multicentre studies. Log-rank analysis indicated that the time to discontinuation because of unwillingness to continue therapy (primary endpoint) was appreciably longer in those receiving esomeprazole 20 or 40mg than in placebo recipients (p < 0.0001 all comparisons in both studies), with markedly fewer patients having discontinued treatment at study end in the esomeprazole than the placebo groups (8 to 15% vs 42 and 52% of patients). The vast majority of patients in both treatment groups who discontinued treatment did so because of inadequate control of heartburn.

Eradication of Helicobacter pylori infection: Seven to 10 days’ treatment with triple therapy regimens that included esomeprazole (20mg twice daily or 40mg once daily) or omeprazole (20mg once daily), plus twice-daily amoxicillin 1g and clarithromycin 500mg, effectively eradicated H. pylori infection in patients with duodenal ulcer disease.

In over 400 patients with endoscopically confirmed duodenal ulcers, eradication of H. pylori occurred in 86 to 90% of recipients of triple therapy regimens including esomeprazole 20mg twice daily for 7 days in two randomised, double-blind, multicentre trials. These eradication rates were similar to those achieved with omeprazole-based triple therapy regimens (eradication rate of 88% in both studies; intention-to-treat analyses).

As expected, 10 days’ treatment with triple therapy including esomeprazole 40mg once daily was significantly (p < 0.001) more effective in eradicating H. pylori infection than 10 days’ dual therapy (esomeprazole plus clarithromycin at the same dosages) [77 vs 52% of patients; intention-to-treat analysis].

Currently, data evaluating the efficacy of esomeprazole-based triple therapy regimens on ulcer healing are limited. Nevertheless, in a well designed trial, triple therapy including esomeprazole (20mg twice daily for 1 week) followed by 3 weeks’ treatment with placebo was as effective for ulcer healing as a similar twice-daily omeprazole-based triple therapy regimen followed by omeprazole 20mg once daily for 3 weeks (91 vs 92% of patients experienced ulcer healing; intention-to-treat analysis).

In general, recipients of esomeprazole-based triple therapy regimens showed an improvement in the frequency and severity of epigastric pain and heartburn from baseline levels in two double-blind trials. In the largest study, markedly fewer patients were experiencing epigastric pain (14 vs 96% of patients at baseline) and heartburn (10 vs 66%) after 4 weeks’ treatment (1 week of esomeprazole-based triple therapy, followed by 3 weeks of placebo) than at baseline. Similar symptomatic improvements from baseline were also experienced in those receiving omeprazole-based triple therapy for 1 week followed by omeprazole 20mg once daily for 3 weeks (epigastric pain experienced by 95% of patients at baseline vs 15% at 4 weeks; heartburn by 68 vs 5%). These improvements were maintained in both treatment groups at 8 to 10 weeks’ follow-up.

Pharmacoeconomic considerations: Pharmacoeconomic studies of esomeprazole are currently limited to preliminary cost analyses based on clinical trial results and/or patient databases.

A decision-analysis model based on pooled data from three 8-week clinical studies in 4877 patients with endoscopically confirmed reflux oesophagitis showed a 14% reduction in direct medical costs with esomeprazole 40mg over omeprazole 20mg daily. The cost saving of £1290 over 8 weeks was increased to £2064 when treatment failure costs were accounted for. Direct medical costs for primary care visits, gastroenterologists visits and upper gastrointestinal endoscopy were based on 1998 UK values, and those for the acquistion of drugs on 2000 values. A further decision-analysis model has shown an apparent saving relative to omeprazole 20mg daily in direct medical costs from a UK National Health Service perspective when esomeprazole 40mg daily is given to patients with a diagnosis of GORD without endoscopic confirmation.

Application of results from two 6-month studies in 770 patients receiving on-demand treatment of GORD with esomeprazole 20mg daily or placebo to a Markov model showed reductions in direct medical costs with esomeprazole of 16 and 35%, respectively, relative to intermittent acute 4-week treatment or continuous therapy with omeprazole 20mg daily. UK direct medical costs for primary care visits, gastroenterologists visits and upper gastrointestinal endoscopy were based on 1998 values, and those for the acquistion of drugs on 2000 values. In addition, an annual cost advantage for esomeprazole 20mg daily over omeprazole 10 or 20mg daily has been shown on the basis of UK drug costs, clinical trial data and drug usage statistics derived from a 1028-patient UK general practice database.

Tolerability

Like other proton pump inhibitors, esomeprazole is well tolerated as reported in both clinical trials and in pooled tolerability data (n = 6682). In two large 8-week randomised trials (n = 2405 and 1957), a similar proportion of patients (≈1 to 2.6%) receiving esomeprazole 20 or 40mg once daily or omeprazole 20mg once daily discontinued treatment due to an adverse event. There was no difference in the nature or frequency of individual adverse events (1.8 to 8.7% of patients) in these trials; headache, diarrhoea, nausea, abdominal pain and respiratory infection were most commonly reported. No treatment-related serious adverse events were reported with esomeprazole or omeprazole therapy in these studies. There were also no clinically relevant changes in laboratory parameters or vital signs with either treatment.

There were no between-group differences in the tolerability profiles of esomeprazole 40mg once daily or lansoprazole 30mg once daily in a large randomised, double-blind trial in >5000 patients with erosive oesophagitis. Ten percent of patients in each treatment group experienced at least one adverse event considered to be drug-related; the most frequently reported adverse events with either esomeprazole or lansoprazole treatment were headache (5.8 vs 4.5%), diarrhoea (4.2 vs 4.7%), respiratory infection (2.8 vs 3.8%), abdominal pain (2.9 vs 2.9%), flatulence (2.3 vs 2.4%) and nausea (2.1 vs 2.5%). Serious adverse events considered to be treatment related occurred in 0.7 and 0.5% of patients in the esomeprazole and lansoprazole groups, respectively, with 1.8 and 1.9% of recipients discontinuing treatment due to adverse events. There were no clinically relevant changes in laboratory parameters or vital signs in either treatment group.

Triple therapy with esomeprazole plus amoxicillin and clarithromycin for 7 or 10 days for the eradication of H. pylori infection was most commonly associated with diarrhoea, taste perversion and abdominal pain according to pooled tolerability data (number of patients not reported). The esomeprazole triple therapy regimen was associated with a similar tolerability profile to that of an equivalent omeprazole-based regimen.

Maintenance therapy with esomeprazole 20 or 40mg once daily for 6 months was generally well tolerated in patients with healed GORD in two randomised, double-blind trials in 318 and 375 patients. The nature of drug-related adverse events experienced with maintenance treatment was no different from that experienced with 4 to 8 weeks’ treatment. A 12-month noncomparative study in 807 patients with healed oesophagitis confirmed that esomeprazole 40mg once daily was well tolerated.

Patients who received esomeprazole as maintenance therapy remained in randomised studies for a much longer time than placebo recipients (mean values: 116 to 161 vs 59 and 61.5 days). Therefore, direct comparisons of adverse event ncidences were difficult to make. After 1 month of treatment, the incidences of the most common adverse events and the proportions of patients who experienced at least one adverse event were similar in the esomeprazole and placebo groups. Over the 6 months’ duration of these trials, esomeprazole was generally associated with higher rates of discontinuation due to adverse events and higher overall frequencies of adverse events than placebo, possibly because of the longer treatment time with the active drug.

Considerably more patients receiving esomeprazole 20mg as required (up to 20 mg/day) than placebo recipients completed a study of symptom-driven on-demand maintenance therapy in patients without erosive oesophagitis. More esomeprazole than placebo recipients experienced adverse events; however, the frequency of events was similar in the two treatment groups when adjusted for exposure to treatment. Respiratory infection was the most common event in both treatment groups.

No enterochromaffin-like cell dysplasia, carcinoids or neoplasia were reported in pooled tolerability data from noncomparative and randomised studies in 1326 patients with healed erosive oesophagitis who received esomeprazole 10, 20 or 40 mg/day or placebo for up to 6 or 12 months. Gastric histological scores with both esomeprazole and placebo fluctuated to a minor extent and there were no concerns relating to development of atrophic gastritis or clinically significant changes in enterochromaffin-like cells.

Dosage and Administration

Dosage recommendations for esomeprazole differ between countries. In the UK, esomeprazole 40mg once daily for 4 to 8 weeks is indicated for the healing of erosive oesophagitis associated with GORD, with a further 4 to 8 weeks at the same dosage considered if oesophagitis is not healed; the recommended dosage in the US is 20 or 40mg once daily for 4 to 8 weeks, with a further 4 to 8 weeks’ treatment considered if oesophagitis is not healed. Esomeprazole 20mg once daily is recommended in both countries for the maintenance of healed erosive oesophagitis. Currently, no controlled studies of >6 months’ duration have been carried out; a noncomparative trial of 12 months’ duration has been conducted. In patients with symptomatic GORD, esomeprazole 20mg once daily for 4 weeks is recommended in both countries. In the UK, subsequent symptom control can be achieved using an ’on-demand’ regimen of 20mg once daily as required.

For the eradication of H. pylori in patients with duodenal ulcer disease, triple therapy with esomeprazole 20mg twice daily plus twice-daily amoxicillin 1g and clarithromycin 500mg for 7 days is recommended in the UK, whereas in the US triple therapy consists of esomeprazole 40mg once daily plus amoxicillin 1g twice daily and clarithromycin 500mg twice daily for 10 days.

Esomeprazole dispersable tablets (multiple unit pellet system) should be swallowed whole at least one hour before eating; the pellets may be mixed with apple sauce for patients who have difficulty in swallowing. In nursing mothers, a decision should be made whether to discontinue nursing or to discontinue treatment. Although animal studies have shown no evidence of fetal abnormality, there are no well controlled trials in pregnant women (category B rating); thus, the drug should be used during pregnancy only if clearly needed. Dosage adjustments are not necessary in patients who are elderly or those with renal or mild to moderate hepatic impairment. In patients with severe hepatic impairment, the dosage of esomeprazole should not exceed 20 mg/day. The tolerability and effectiveness of esomeprazole have not been established in paediatric patients.

Concurrent administration of esomeprazole with warfarin, quinidine, clarithromycin or amoxicillin does not produce any clinically significant interactions. Esomeprazole may, however, interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g. ketoconazole, itraconazole, digoxin and iron salts). Plasma concentrations of phenytoin should be monitored when initiating or discontinuing coadministration of esomeprazole.

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Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Lesley J. Scott
    • 1
  • Christopher J. Dunn
    • 1
  • Gordon Mallarkey
    • 1
  • Miriam Sharpe
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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