Pantoprazole

Pantoprazole is a substituted benzimidazole proton pump inhibitor that irreversibly inhibits the gastric H+/K+ ATPase. It is the PPI with the least clinically relevant cytochrome P450 inhibition and is widely available for IV use, which makes it a common choice in hospital and with interacting drugs.

Classification. Proton pump inhibitor; gastric antisecretory agent.

Mechanism. Prodrug activated in the acidic parietal cell canaliculus to a cyclic sulphenamide that binds the pump covalently. Activation needs a lower pH than most PPIs, so it is relatively stable at near-neutral pH.

Pharmacodynamics. Full effect after 3 to 5 days of daily dosing; acid suppression outlasts plasma levels and secretion recovers over several days after stopping.

Pharmacokinetics. Oral bioavailability about 77% and unchanged with repeated dosing. Protein binding about 98%; half-life about 1 hour, prolonged in cirrhosis.

Metabolism. Hepatic, mainly CYP2C19 demethylation followed by sulphate conjugation, with a CYP3A4 contribution. Conjugation gives a low potential for CYP inhibition. 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 to 40 mg once daily.

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

Peptic ulcer disease.

• Duodenal ulcer: 40 mg orally once daily for 2 to 4 weeks.

• Gastric ulcer: 40 mg orally once daily for 4 to 8 weeks, with endoscopic confirmation of healing.

NSAID-associated ulcer prophylaxis. 20 mg orally once daily for as long as the NSAID continues in those at raised gastrointestinal risk.

Helicobacter pylori eradication. Pantoprazole 40 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.

Zollinger-Ellison syndrome.

• Oral: start 80 mg daily (40 mg twice daily) and titrate to acid output; usual 80 to 160 mg daily in divided doses. Doses up to 240 mg daily have been used.

• IV: 80 mg twice daily, increased to 80 mg three times daily if needed.

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

Suspected upper gastrointestinal bleeding before endoscopy. 80 mg IV bolus then infusion, or 40 mg IV twice daily, is usual practice where endoscopy is delayed. It reduces high-risk stigmata at endoscopy but does not reduce rebleeding, surgery or mortality, and must not delay endoscopy.

Stress ulcer prophylaxis in critical care. 40 mg IV or orally once daily, only in those at high risk: mechanical ventilation over 48 hours, coagulopathy (platelets under 50 x 10^9/L or INR over 1.5), shock, severe burns or major head or spinal injury. Stop when risk factors resolve or on discharge from critical care.

Parenteral use when oral route unavailable. 40 mg IV once daily, switching to oral as soon as possible.

Paediatric dosing (erosive oesophagitis, age 5 years and over).

• Body weight 15 to under 40 kg: 20 mg orally once daily for up to 8 weeks.

• Body weight 40 kg and over: 40 mg orally once daily for up to 8 weeks.

• IV, when oral route unavailable: about 1 mg/kg once daily, maximum 40 mg 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; injection site thrombophlebitis with IV use.

Serious adverse effects.

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

• Clostridioides difficile infection and hospital-acquired pneumonia; association with pneumonia is a reason to stop stress ulcer prophylaxis promptly.

• Acute interstitial nephritis.

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

• Rare hepatocellular injury.

Major interactions.

• Clopidogrel: no clinically significant reduction in activation; pantoprazole is the PPI of choice with clopidogrel.

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

• Warfarin: occasional INR rise; monitor INR when starting or stopping.

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

Special groups.

• Pregnancy: human data are more limited than for omeprazole; use when clearly needed. Omeprazole has the most reassuring pregnancy data.

• Breastfeeding: low milk transfer; compatible.

• Children: weight-based dosing; licensed ages vary by product and region.

• Older adults: no dose change; review continued need, particularly on discharge from hospital.

• Kidney impairment: no dose adjustment; not removed by dialysis.

• Liver impairment: severe impairment, maximum 20 mg daily orally or IV; monitor liver enzymes and stop if they rise.

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

Oral administration. Take 30 to 60 minutes before breakfast; a second daily dose goes before the evening meal. Swallow tablets whole; do not crush or chew. Granules may be sprinkled on apple purée or given in apple juice. Use granules for enteral tubes, never crushed tablets.

IV administration.

• Bolus: reconstitute 40 mg in 10 mL sodium chloride 0.9% and give over at least 2 minutes.

• Intermittent infusion: further dilute in 100 mL sodium chloride 0.9% or glucose 5% and infuse over about 15 minutes.

• Continuous infusion for bleeding: 80 mg in 100 mL sodium chloride 0.9% (0.8 mg/mL) at 10 mL/hour gives 8 mg/hour.

• Use reconstituted solution within 12 hours. Give through a dedicated line or flush before and after; do not mix with other drugs.

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

Monitoring.

• Review indication within 72 hours of IV use and switch to oral when eating.

• Stop stress ulcer prophylaxis when risk factors resolve; review all hospital-started PPIs before discharge.

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

• Liver enzymes in severe liver impairment.

• 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. Urgent endoscopy for suspected upper gastrointestinal bleeding, ideally within 24 hours of presentation and sooner with haemodynamic instability. Endoscopy for alarm features or failure of 8 weeks of twice daily therapy.