Rabeprazole

Rabeprazole is a substituted benzimidazole proton pump inhibitor that irreversibly inhibits the gastric H+/K+ ATPase. It activates over a wider pH range than other PPIs, giving a faster onset, and its clearance depends less on CYP2C19, so response varies less with genotype.

Classification. Proton pump inhibitor; gastric antisecretory agent.

Mechanism. Prodrug converted to an active sulphenamide in the parietal cell canaliculus that binds the pump covalently. Its higher pKa allows activation at a less acidic pH, producing near-maximal inhibition from the first day.

Pharmacodynamics. Onset of acid suppression within an hour of the first dose; full steady effect after a few days. Acid secretion recovers over 2 to 3 days after stopping.

Pharmacokinetics. Oral bioavailability about 52%, unaffected by food. Protein binding 96%; half-life about 1 hour, prolonged in chronic liver disease.

Metabolism. Mainly nonenzymatic reduction to a thioether, with minor CYP2C19 and CYP3A4 metabolism. About 90% of metabolites are excreted in urine. Weak CYP inhibition.

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

GORD with erosive oesophagitis. 20 mg once daily for 4 to 8 weeks. Maintenance 10 to 20 mg once daily.

Nonerosive reflux. 10 mg once daily for 4 weeks (20 mg once daily is used in some regions); thereafter 10 mg on demand.

Peptic ulcer disease.

• Duodenal ulcer: 20 mg once daily for 4 weeks, extended to 8 weeks if not healed.

• Gastric ulcer: 20 mg once daily for 6 weeks, extended to 12 weeks if not healed, with endoscopic confirmation of healing.

Helicobacter pylori eradication. Rabeprazole 20 mg twice daily 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. Lower dependence on CYP2C19 is an advantage in rapid metabolisers.

Zollinger-Ellison syndrome. Start 60 mg once daily and titrate to acid output; up to 120 mg daily given as 60 mg twice daily. Doses up to 100 mg once daily have also been used.

Upper gastrointestinal bleeding, oral phase after IV therapy. 20 mg twice daily to day 14, then 20 mg once daily to complete 6 to 8 weeks. No IV formulation is widely available.

Paediatric dosing. Age 12 years and over: GORD 20 mg once daily for up to 8 weeks. Use under age 12 is limited and product-specific.

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, pharyngitis and nonspecific pain.

Serious adverse effects.

• Hypomagnesaemia, Clostridioides difficile infection and acute interstitial nephritis.

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

Major interactions.

• Clopidogrel: interaction is weak; pantoprazole is still preferred where available.

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

• Warfarin: occasional INR rise; monitor INR.

• Digoxin: modest rise in levels from raised gastric pH; monitor in those at risk of toxicity.

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

Special groups.

• Pregnancy: limited human data; prefer omeprazole, which has the most data.

• Breastfeeding: no human data; prefer omeprazole or pantoprazole.

• Children: limited to adolescents in most markets.

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

• Kidney impairment: no dose adjustment.

• Liver impairment: no fixed adjustment; use caution in severe impairment and start at the lowest dose.

• Ancestry: less affected by CYP2C19 genotype, relevant where poor or rapid metaboliser alleles are common.

Formulations. Gastro-resistant tablets 10 mg and 20 mg.

Oral administration. Take in the morning before eating; a second daily dose goes before the evening meal. Food does not change absorption, but timing before a meal improves pump inhibition. Swallow whole; do not crush, chew or split. Not suitable for enteral tubes.

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.

• 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.