Esomeprazole

Esomeprazole is the S isomer of omeprazole, a proton pump inhibitor that irreversibly inhibits the gastric H+/K+ ATPase. Slower hepatic clearance than the racemate gives higher and more consistent exposure at equivalent doses, with greater time at intragastric pH over 4.

Classification. Proton pump inhibitor; gastric antisecretory agent.

Mechanism. Prodrug concentrated and activated in the acidic secretory canaliculus to a sulphenamide that binds the pump covalently. Inhibition persists until new pumps are synthesised.

Pharmacodynamics. Maximal acid suppression after about 5 days of daily dosing. Once daily 40 mg maintains intragastric pH over 4 for more of the day than omeprazole 20 mg; the clinical advantage over equivalent doses of other PPIs is modest.

Pharmacokinetics. Oral bioavailability about 64% after a single 40 mg dose, rising to about 89% with repeated dosing. Food reduces absorption. Protein binding 97%; half-life about 1.3 hours.

Metabolism. Hepatic via CYP2C19 and CYP3A4; S isomer depends less on CYP2C19 than the R isomer, but genotype still alters exposure. Inhibits CYP2C19. About 80% of metabolites are excreted in urine.

Adult doses unless stated. Use the lowest effective dose for the shortest necessary duration.

GORD with erosive oesophagitis. 40 mg orally once daily for 4 weeks, continued for a further 4 weeks if not healed. Maintenance 20 mg once daily.

Nonerosive reflux. 20 mg orally once daily for 4 weeks; thereafter 20 mg on demand.

NSAID-associated ulcer. Healing 20 mg orally once daily for 4 to 8 weeks. Prophylaxis 20 mg once daily for as long as the NSAID continues in those at raised risk.

Helicobacter pylori eradication. Esomeprazole 20 mg twice daily (40 mg twice daily often used to improve eradication) for 14 days, combined with one of:

• Amoxicillin 1 g twice daily plus clarithromycin 500 mg twice daily.

• Penicillin allergy: clarithromycin 500 mg twice daily plus metronidazole 400 to 500 mg twice daily.

• Bismuth quadruple therapy where clarithromycin resistance is high or after a failed first attempt: bismuth subsalicylate 524 mg four times daily, tetracycline 500 mg four times daily and metronidazole 400 to 500 mg three times daily.

Clarithromycin resistance is reported to be high in several East African settings, so bismuth quadruple therapy or a 14-day course is advised where local susceptibility data are lacking.

Zollinger-Ellison syndrome. Start 40 mg orally twice daily and titrate to acid output; usual 80 to 160 mg daily, giving doses over 80 mg daily in two divided doses. Doses up to 240 mg daily have been used.

Upper gastrointestinal bleeding from peptic ulcer after endoscopic haemostasis (high-risk stigmata). 80 mg IV infused over 30 minutes, then 8 mg/hour continuous infusion for 72 hours, or intermittent 40 mg IV twice daily. Then oral esomeprazole 40 mg twice daily to day 14, then 40 mg once daily to complete 6 to 8 weeks.

Parenteral use when oral route unavailable. 20 to 40 mg IV once daily (40 mg for erosive oesophagitis), switching to oral as soon as possible.

Paediatric dosing.

• Age 1 to 11 years, body weight 10 to under 20 kg: 10 mg once daily for 8 weeks.

• Age 1 to 11 years, body weight 20 kg and over: 10 to 20 mg once daily for 8 weeks.

• Age 12 to 17 years: 20 to 40 mg once daily; erosive oesophagitis 40 mg once daily for 4 to 8 weeks.

• IV, age 1 to 11 years: under 20 kg 10 mg once daily; 20 kg and over 10 to 20 mg once daily.

Contraindications. Hypersensitivity to any PPI; coadministration with rilpivirine. Avoid with atazanavir and nelfinavir.

Before starting. Endoscopy first for alarm features: new dyspepsia over age 55, weight loss, dysphagia, bleeding, iron deficiency anaemia, persistent vomiting or a mass.

Common adverse effects. Headache, diarrhoea, nausea, abdominal pain, flatulence, constipation and dry mouth.

Serious adverse effects.

• Hypomagnesaemia with prolonged use, particularly with diuretics or digoxin.

• Clostridioides difficile infection.

• Acute interstitial nephritis.

• Vitamin B12 deficiency, fracture, subacute cutaneous lupus erythematosus, microscopic colitis and rebound hypersecretion with long-term use.

Major interactions.

• Clopidogrel: reduces active metabolite formation, similar to omeprazole. Avoid; use pantoprazole.

• Cilostazol: raised levels; reduce cilostazol dose.

• Citalopram and escitalopram: raised levels with QT risk; consider lower SSRI doses.

• Methotrexate at high dose: reduced clearance; withhold esomeprazole around high-dose courses.

• Raised diazepam, phenytoin and tacrolimus levels; INR rise with warfarin. Monitor levels and INR.

• Reduced absorption of ketoconazole, itraconazole capsules, atazanavir, rilpivirine, erlotinib, dasatinib, oral iron and mycophenolate mofetil.

Special groups.

• Pregnancy: data derived largely from omeprazole are reassuring; acceptable when clearly needed.

• Breastfeeding: low milk transfer; compatible.

• Children: weight-based dosing from age 1 year.

• Older adults: no dose change; review continued need regularly.

• Kidney impairment: no dose adjustment.

• Liver impairment: severe impairment, maximum 20 mg daily orally or IV. For bleeding in severe impairment, give the 80 mg bolus and limit the infusion to 4 mg/hour.

Formulations. Gastro-resistant tablets 20 mg and 40 mg; gastro-resistant capsules; gastro-resistant granules for oral suspension; powder for IV injection or infusion 40 mg.

Oral administration. Take at least 1 hour before a meal, usually breakfast; a second daily dose goes before the evening meal. Swallow whole. Tablets may be dispersed in noncarbonated water, stirred and drunk within 30 minutes, without crushing the pellets. Dispersed tablets or granules may be given through enteral tubes.

IV administration.

• Injection: reconstitute 40 mg in 5 mL sodium chloride 0.9% and give over at least 3 minutes.

• Infusion: dilute in up to 100 mL sodium chloride 0.9% and give over 10 to 30 minutes.

• Bleeding: 80 mg loading dose over 30 minutes, then 8 mg/hour by continuous infusion.

• Use reconstituted solution within 12 hours. Give through a dedicated line or flush before and after.

Baseline. No routine tests. Magnesium before long-term use with digoxin or diuretics.

Monitoring.

• Review indication and continued need at 4 to 8 weeks, then at least annually.

• Magnesium periodically on long-term therapy in those at risk.

• Vitamin B12 if anaemia or neuropathy develops on prolonged use.

• Stop 2 weeks before H. pylori breath or stool antigen testing, and at least 5 days before chromogranin A measurement.

Therapeutic drug monitoring. Not applicable.

Stopping. After long-term use, step down or halve the dose for 2 to 4 weeks before stopping, using antacids for rebound symptoms. Stop at once if interstitial nephritis, C. difficile infection or cutaneous lupus is suspected.

Referral and escalation. Endoscopy for alarm features or failure of 8 weeks of twice daily therapy. Refractory reflux needs pH impedance testing before escalation to surgery.