Esomeprazole (Nexium)
UK Medicines Information, 2001 See article at www.ukmi.nhs.uk
þÿ Produced by the UK Medicines Information Pharmacists Group NEW MEDICINES ON THE MARKET Evaluated information for the NHS ESOMEPRAZOLE Summary · Esomeprazole is the S-isomer of omeprazole. The range of licensed indications for esomeprazole is more limited than that for omeprazole and excludes prevention and treatment of NSAID-associated gastric and duodenal ulceration, healing of gastric/duodenal ulcers other than duodenal ulcers associated with H. pylori, and Zollinger-Ellison syndrome. · European patent protection for omeprazole expires in 2002 when cheaper, generic versions are likely to be made available. At current prices, esomeprazole at a dose of 40mg daily and omeprazole at a dose of 20 mg daily are cost equivalent for 28 days' treatment. · Evaluation of esomeprazole studies is complicated both by the fact that, currently, many are published in abstract form only, and by the issue of the doses chosen in the comparative studies. · Unlike omeprazole and other PPIs on the market, esomeprazole is licensed for 'on-demand' symptomatic control of gastro-oesophageal reflux disease (GORD) in patients without oesophagitis. Only placebo-controlled studies support the use of esomeprazole in this way. `On-demand' use of esomeprazole will necessitate determining the patients for whom such use of a PPI is appropriate, i.e. those without oesophagitis. Although cost benefits may be derived from the use of esomeprazole on an `on-demand' basis in patients with mild GORD, NICE guidance recommends other treatments first in such patients. · At a dose of 40mg daily, esomeprazole has been found to be statistically significantly more effective than omeprazole 20mg daily at healing erosive oesophagitis in patients with GORD. There are no published studies comparing esomeprazole with PPIs other than omeprazole in this indication, but healing and maintenance rates are broadly similar to other PPIs. Date Published: February 2001 Monograph Number : 04/01/03 Marketed; September 2000 Region of origin to whom queries should be directed: Wales The information contained in this document will be superseded in due course. Not to be used for commercial purposes Copyright MIPG 2001 Web site http://www.ukmi.nhs.uk/med_info/stage4.html ESOMEPRAZOLE APPROVED NAME: Esomeprazole BRAND NAME (MANUFACTURER): Nexium SYNONYMS H 19918, perprazole, S-omeprazole magnesium PRESENTATION: Gastro-resistant tablets containing either 20mg or 40mg of esomeprazole. BNF THERAPEUTIC CLASS Proton pump inhibitor (BNF 1.3.5) LICENSED INDICATIONS In patients with Gastro-oesophageal Reflux Disease (GORD): treatment of erosive reflux oesophagitis, long-term management of patients with healed oesophagitis to prevent relapse and symptomatic treatment [1]. Healing of Helicobacter pylori -associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with H. pylori -associated ulcers (with appropriate antibacterial regimen) [1]. DOSAGE AND ADMINISTRATION GORD: Treatment of erosive reflux oesophagitis: 40 mg od for 4 weeks or 8 weeks. Prevention of relapse in patients with healed oesophagitis: 20 mg od. Symptomatic treatment: 20 mg once daily (patients without oesophagitis). Once symptoms resolved: 20 mg once daily on demand [1]. H. pylori -associated ulcers: 20 mg esomeprazole with 1g amoxycillin and 500 mg clarithromycin, all twice daily for 7 days [1]. THERAPEUTIC COMMENT Esomeprazole is the fifth proton pump inhibitor (PPI) on the UK market, but the first to be licensed for the symptomatic treatment of GORD, without oesophagitis, on an 'on-demand' basis. On-demand use could offer cost benefits, but consideration should be given to drug interactions in patients taking esomeprazole in this way as they will not have become stabilised on the drug. Esomeprazole is the only single isomer PPI and appears to possess more pronounced and sustained acid suppressing effects than omeprazole [2,3,4], which loses its European patent protection in 2002 [5]. Unlike lansoprazole and omeprazole, esomeprazole is not licensed for the treatment and prevention of NSAID- associated ulcers. SECTOR OF USE Hospital [Y] Primary Care [Y] COST AND COURSE DETAILS 28 days' treatment: £18.50 (20 mg), £28.56 (40 mg)* TREATMENT ALTERNATIVES Drug Dose Cost (£, 28 days) * Lansoprazole 30 mg/day 23.75 Omeprazole 20 mg/day 28.56 Pantoprazole 40 mg/day 23.65 Rabeprazole 20 mg/day 22.75 * Prices from MIMS February 2001 Page 2 of 8 ESOMEPRAZOLE INTRODUCTION In healthy volunteers, acid control with esomeprazole 40 mg daily was superior to that with Patients experiencing acid-related gastrointestinal lansoprazole 30 mg daily (p<0.001) [10] and disorders invariably initially present with dyspepsia. rabeprazole 20 mg daily (p=0.005) [11]. It is estimated that 40% of the adult population PHARMACOKINETICS experience dyspepsia each year. GORD is believed to be the cause in 15-20% of these cases and gastric Absorption and metabolism: Peak plasma and duodenal ulcers in a further 15-25% [6]. Only concentrations of esomeprazole are reached 1-2 10% of patients who consult their GP because of hours after oral administration and the plasma dyspepsia are referred for endoscopy. For GORD to elimination half-life is 1.3 hours after repeated once be diagnosed, it should be shown that oesophagitis daily dosing. Following 5 days' dosing with or acid reflux are present and heartburn symptoms esomeprazole 20 mg daily, the area under the must be predominant [7]. plasma concentration-time curve (AUC) is 80% higher than with omeprazole 20 mg [4]. Food NICE guidelines support the use of a healing dose delays and decreases absorption of esomeprazole, of PPI in patients with severe GORD symptoms or but does not appear to significantly alter the drug's a proven pathology, e.g. oesophageal ulceration. effect on intragastric acidity [1]. Once symptoms are controlled, it is recommended that these patients receive a lower, maintenance Esomeprazole is metabolised by the cytochrome dose of PPI. The least expensive appropriate PPI P450 system; the enzyme CYP2C19 is mainly should be used, within licensed indications [6]. responsible for its metabolism, but CYP3A4 is also involved [1]. PHARMACOLOGY Elderly patients: Metabolism was not significantly Esomeprazole is a weak base, which is converted to altered in 13 elderly patients (71 to 80 years) [12]. its active form in the acidic environment of the gastric parietal cell. Like other PPIs, esomeprazole Renal impairment: No relevant studies have been inhibits basal and stimulated acid secretion by conducted, but less than 1% of the parent drug is binding to the H+/K+-ATPase enzyme in the parietal found in urine [1]. cell [1]. Hepatic impairment: The AUC increased by 76% Esomeprazole 40 mg and 20 mg once daily and the t1/2 by 29% in 12 patients with mild to maintained intragastric pH levels at above 4 for severe hepatic dysfunction [13]. However, when significantly longer than omeprazole 20 mg once patients were grouped according to the degree of daily (p<0.001 and p<0.01, respectively) in 36 liver function, AUC and t1/2 values for patients with patients with GORD symptoms [4]. mild and moderate liver function were in the same range as those for GORD patients with no liver Similarly designed studies found that esomeprazole impairment. Dosage adjustment is not required in 40 mg daily provided more sustained acid patients with mild/moderate liver impairment. suppression than pantoprazole 40 mg daily However, a maximum dose of 20 mg esomeprazole (p<0.001) [8] and omeprazole 40 mg daily should not be exceeded in patients with severe liver (p<0.001) [9] in patients with symptoms of GORD. impairment [1]. Page 3 of 8 ESOMEPRAZOLE EFFICACY days without heartburn (investigator assessment, p<0.001). [16,17] Eight published studies covering the licensed indications of esomeprazole are discussed below Symptomatic treatment of GORD (please also see Table 1). Currently, all but one of these studies are published in abstract form only, a In two double-blind, six month studies, factor that limited assessment as complete outcome `endoscopically negative' patients in whom details and the statistical analyses carried out are heartburn had completely resolved after four weeks not given in all cases. Please note that unlicensed of treatment with esomeprazole or omeprazole were esomeprazole doses are used in some of the studies. randomised to receive esomeprazole or placebo on demand [18,19]. The time to study discontinuation Treatment of erosive reflux oesophagitis in because of inadequate heartburn control or for any patients with GORD reason was statistically significantly longer for both esomeprazole groups (20 and 40 mg daily) in the Two large, randomised, double-blind studies found first study than for the placebo group (p<0.0001). that endoscopic appearance was normal in a Antacid usage was over two-fold greater in the statistically significantly greater proportion of esomeprazole groups, but the percentage of placebo patients receiving esomeprazole 40 mg daily than patients who did not discontinue treatment because those receiving omeprazole 20 mg daily at week 4 of inadequate heartburn control was at least 49% in and by week 8 [14, 15]. The percentage of patients both studies. In the first study, patients took a mean experiencing heartburn resolution, as assessed by of 0.33 and 0.29 doses/day in the esomeprazole 20 investigators at week 4 was also statistically mg and 40 mg groups, respectively. significantly higher for patients receiving esomeprazole 40 mg daily than for those receiving Healing of H. pylori -associated duodenal ulcer omeprazole (68.3% vs 58.1%, p<0.001 [15]). and prevention of relapse of peptic ulcer Esomeprazole 20 mg daily did not differ significantly from omeprazole 20mg in terms of A randomised, double-blind study found that healing or investigator-assessed heartburn neither healing nor H. pylori eradication rates resolution at week four [14]. differed significantly between patients receiving triple therapy with esomeprazole or omeprazole Maintenance therapy in patients with GORD [20]. H. pylori eradication was determined by [13C]- and healed oesophagitis urea breath test and histology at four weeks after the end of therapy. Two randomised, double-blind, six-month studies found esomeprazole 10, 20 and 40 mg daily to be A further randomised, double-blind study statistically significantly more effective than comparing the effects of seven-day triple therapy placebo at maintaining healing in patients with with esomeprazole or omeprazole was conducted in endoscopically proven healed erosive oesophagitis 448 H. pylori -positive patients with inactive (p<0.001). The percentage of patients maintaining duodenal ulcer disease [21]. Eradication of H. healing at six months was markedly higher in the pylori infection was confirmed by negative [13C]- esomeprazole 20 and 40 mg groups [16, 17]. A urea breath tests at weeks four and eight. No statistically significant difference between each of statistically significant difference in eradication rate the esomeprazole groups and the placebo group was was noted between the groups. also found at one month for the proportion of patients who had experienced seven consecutive Page 4 of 8 ESOMEPRAZOLE PROMOTIONAL DATA ADVERSE EFFECTS Esomeprazole promotional material focuses on use The summary of product characteristics for of the drug on an on-demand basis, its value for esomeprazole lists the following adverse effects, money, its sustained acid suppressing efficacy and stating that in clinical trials, none were found to be there being no need for follow-up monotherapy in dose-related [1]. the healing of H. pylori -associated duodenal ulcer with esomeprazole. Common (>1/100, <1/10): Headache, abdominal pain, diarrhoea, flatulence, nausea/vomiting, The `on-demand' use of esomeprazole is supported constipation. by placebo-controlled studies. There may be some Uncommon (>1/1000, <1/100): Dermatitis, pruritus, cost advantages associated with the use of the drug urticaria, dizziness, dry mouth. in this way. It should be stressed, however, that on- demand therapy is only licensed in patients without Adverse effects seen with omeprazole are also listed oesophagitis. As with other PPIs, for patients with and may occur. Sinusitis and respiratory infection oesophagitis, the licensed doses are daily. There have been reported [16,17]. A twelve-month safety have been no studies comparing on-demand study in GORD patients with healed oesophagitis esomeprazole in GORD without oesophagitis to concluded that the adverse effect profile for other PPIs or to other, less intensive treatments esomeprazole was similar to that previously (antacids, histamine H2-antagonists, etc). reported for other PPIs [22]. Randomised, cross-over studies indicate that esomeprazole 40 mg daily suppresses acidity for longer periods than omeprazole 20 or 40 mg daily CONTRAINDICATIONS AND [4], pantoprazole 40 mg daily [8] and lansoprazole PRECAUTIONS 30 mg daily [10] and rabeprazole [11], although only one of these studies has been published in full. · Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other Any healing advantages over existing PPIs that the constituents of the product. sustained acid suppressing effect of esomeprazole · Breast feeding. 40 mg daily offers in erosive oesophagitis could be outweighed by the cost of the healing dose and it may be advisable to await further evidence of this PRECAUTIONS AND INTERACTIONS advantage. [1] In one study, duodenal ulcer healing was achieved · Pregnancy. after seven days' triple therapy with esomeprazole, · Exclude malignancy if patients present with any however the apparent lack of need for further PPI alarm symptom and when gastric ulcer is monotherapy in these circumstances may not be suspected/present. specific to esomeprazole [20]. Omeprazole and · Keep patients on long-term treatment under esomeprazole appear to be equally effective at surveillance. eradicating H. pylori in patients with inactive · On-demand treatment: Instruct patients to duodenal ulceration [21]. contact doctor if symptoms change and consider drug interactions. Page 5 of 8 ESOMEPRAZOLE · Triple therapy: Also consider drug interactions 17. Johnson DA et al. Efficacy and safety of esomeprazole as maintenance therapy in GERD patients with healed erosive eosophagitis. for other drugs in the therapy, e.g. Gastroenterology 2000; 118 (4; suppl 2): A330 clarithromycin. 18. Talley NJ et al. Esomeprazole 40 mg and 20 mg is efficacious in the · long-term management of patients with endoscopically-negative GERD: Drugs for which gastric acidity affects A placebo-controlled trial of on-demand therapy for 6 months. absorption, e.g. ketoconazole, itraconazole. Gastroenterology 2000;118 (4; suppl 2): A3608 19. Talley NJ et al. Esomeprazole 20 mg maintains symptom control in · Drugs metabolised by CYP2C19 enzyme, e.g. endoscopy-negative GERD: A randomised placebo-controlled trial of diazepam, citalopram, imipramine, on-demand therapy for 6 months. Gastroenterology 2000;118 (suppl 2):A348 clomipramine, phenytoin. Monitor phenytoin 20. Tulassay Z et al. 7-day treatment with esomeprazole-based triple plasma concentrations during esomeprazole therapy eradicates H. Pylori (HP) and heals patients with duodenal ulcer (DU) disease. Gastroenterology 2000;118 (4; suppl 2):A2691 introduction or withdrawal. 21. Veldhuyzen SJ et al. 7-day triple therapy with esomeprazole, · Rare hereditary problems of fructose amoxicillin and clarithromycin for H. pylori (HP) eradication in duodenal ulcer. Gastroenterology 2000;118 (4; suppl 2):A2694 intolerance, glucose-galactose malabsorption or 22. Maton P et al. Safety and efficacy of long-term treatment with sucrase-isomaltase insufficiency. esomeprazole in patients with healed erosive esophagitis (EE). Gastroenterology 2000;118 (4; suppl 2): A337 References 1. AstraZeneca. Summary of Product Characteristics. Nexium tablets. July 2000. 2. Andersson T et al. Pharmacokinetics (PK) and dose-response relationship of esomeprazole. Gastroenterology 2000;118 (4; suppl 2): A5550 3. Andersson T et al. Pharmacokinetics (PK) and effect on pentagastrin stimulated peak acid output (PAO) of omeprazole (O) and its 2 optical isomers, S-omeprazole/esomeprazole (E) and R-omeprazole (R-O). Gastroenterology 2000:118(4; suppl 2): A5551 4. Lind T et al. Esomeprazole provides improved acid control vs omeprazole in patients with symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000;14:861-867 5. Anon. Adis R + D Insight-esomeprazole. Updated August 2000. 6. National Institute for Clinical Excellence. Guidance on the use of proton pump inhibitors in the treatment of dyspepsia. June 2000 7. Kinnear M et al. Gastro-eosophageal reflux disease. Pharm J 1999;263:241-250. 8. Wilder-Smith C et al. Esomeprazole (E) 40 mg provides more effective acid control than pantoprazole (P) 40 mg. Gastroenterology 2000:118 (4; suppl 2):A352 9. Röhss K et al. Esomeprazole 40mg provides more effective acid control than omeprazole 40mg. Poster presented at the XXXII Nordic Meeting of Gastroenterology, Göteborg 18-21 June 2000. 10. Röhss K et al. Esomeprazole 40 mg provides more effective acid control than lansoprazole 30 mg. Gastroenterology 2000:118 (4; suppl 2):A344 11. Wilder-Smith C et al. Esomeprazole 40 mg provides more effective acid contol than rabeprazole 20 mg. Gut 2000;47 (suppl III):P51 12. Hasselgren G et al. Pharmacokinetics of esomeprazole are not affected by age: an assessment in the elderly. Gastroenterology 2000:118(4; suppl 2):A5698 13. Sjovall H et al. Pharmacokinetics of esomeprazole in patients with liver cirrhosis. Gastroenterology 2000;118 (4; suppl 2): A346 14. Kahrilas PJ et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther 2000;14:1249- 1258 15. Richter JE et al. Esomeprazole is superior to omeprazole for the healing of erosive esophagitis in GERD patients. Gastroenterology 2000;118 (4; suppl 2): A343 16. Vakil N et al. Esomeprazole is effective as maintenance therapy in GERD patients with healed erosive esophagitis (EE). Gastroenterology 2000;118 (4; suppl 2): A350 Page 6 of 8 ESOMEPRAZOLE Table 1 Ref No. Study Design Study Population Study Length Treatment Regimen Outcome (ITT analysis) Erosive Reflux Oesophagitis and GORD RA, DB, PG, GORD, 1960 pts 8 weeks Percentage of patients healed (Cumulative life table estimates) 14 C, MC Endoscopically 4 weeks 8 weeks confirmed erosive 20 mg E od (n = 656) 70.5 89.9* oesophagitis 40 mg E od (n = 654) 75.9* 94.1* 20 mg O od (n = 650) 64.7 86.9 (*p0.05 vs 20 mg O od) 15 (abs) RA, DB, PG, GORD, 2425 pts 8 weeks 40 mg E od (n = 1216) 81.7* 93.7* C, MC Endoscopically 20 mg O od (n = 1209) 68.7 84.2 (*p<0.001 vs 20 mg O od)) confirmed erosive oesophagitis Maintenance Therapy 16 (abs) RA, DB, PG, GORD, 375 pts 6 months Complete healing maintained % pts with sustained heartburn PC, MC (Healed erosive at 6 months (%) * p<0.001 vs resolution (investigator oesophagitis) placebo assessment at 1 month) 10 mg E od (n = 91) 54.2* 50.6* * p<0.001 vs placebo 20 mg E od (n = 98) 78.7* 63.7* 40 mg E od (n = 92) 87.9* 71.3* placebo od (n = 94) 29.1 15.5 17 (abs) RA, DB, PG, GORD, 318 pts 6 months 10 mg E od (n = 77) 57.1* 51.4* PC, MC (Healed oesophagitis) 20 mg E od (n = 82) 93.2* 61.3* 40 mg E od (n = 82) 93.6* 78.7* placebo od (n = 77) 29.0 17.8 *p<0.001 vs placebo *p<0.001 vs placebo Page 7 of 8 ESOMEPRAZOLE Table 1 Continued Ref No. Study Design Study Population Study Length Treatment Regimen Outcome (ITT analysis) Symptomatic Treatment of GORD 18 (abs) RA, DB, PG, GORD, 721 pts 6 months 20 mg E (n = 282) During the 6 month period, the percentage of pts discontinuing PC, MC (Endoscopically 40 mg E (n = 293) because of inadequate heartburn control was 5, 9 and 36 in the E20 negative) placebo (n = 146) mg, E40mg and placebo groups, respectively (p<0.0001, E20/40 mg All on-demand (max 1 dose vs placebo) od) 19 (abs) RA, DB, PG, GORD, 342 pts 6 months 20 mg E (n=170) During the 6 month period, the percentage of pts discontinuing PC, MC (Endoscopically placebo (n=172) treatment because of inadequate heartburn control was 14 in the negative) On demand (max 1 dose od) E20mg group and 51 in the placebo group (p<0.0001, E vs placebo) Ulcer Healing/Prevention of relapse 20 (abs) RA, DB, PG, Duodenal ulcer ( 4 weeks (1 week 20 mg E bd + A and Cl, Ulcer healing and H. pylori eradication occurred in 91% (95% CI 87- C, MC 0.5cm diameter) and H. triple therapy followed by 3 weeks placebo 95%) and 86% (95% CI 81-90%) of pts in the E group and 92% pylori -positive, plus 3 weeks (n = 222) (95% CI 88-95%) and 88% (95% CI 83-92%) of those receiving O. 446 pts monotherapy/ 20 mg O bd + A and Cl, placebo) followed by 3 weeks O 20 mg (n = 224) 21 (abs) RA, DB, PG, H. pylori -positive. 7 days triple 20 mg E bd + A and Cl (n = H. pylori eradication rates (% pts) were 89.7% (95% CI 84.7-93.5%) C, MC History of duodenal therapy 224) and 87.8% (95% CI 82.3-92.0%) in the E and O groups, respectively. ulcer, 448 pts 20 mg O bd + A and Cl (n = 224) Key: RA = randomised PC = placebo controlled = (LA classification grades A-D) E = esomeprazole A = amoxycillin 1000 mg bd DB = double blind C = comparative O = omeprazole Cl = clarithromycin 500 mg bd PG = parallel group MC = multicentre Page 8 of 8
