Vonoprazan
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Healing of all grades of EE and relief of associated heartburn | Adults | Monotherapy | FDA Approved |
| Maintenance of healed EE and relief of associated heartburn | Adults | Monotherapy | FDA Approved |
| Relief of heartburn associated with non-erosive GERD | Adults | Monotherapy | FDA Approved |
| H. pylori infection — triple therapy | Adults | With amoxicillin + clarithromycin | FDA Approved |
| H. pylori infection — dual therapy | Adults | With amoxicillin | FDA Approved |
Vonoprazan is the first potassium-competitive acid blocker (P-CAB) approved in the United States, representing a new mechanistic class distinct from proton pump inhibitors. Unlike PPIs, vonoprazan does not require acid-mediated activation, binds to both active and resting proton pumps in a reversible and potassium-competitive manner, is acid-stable, and achieves meaningful acid suppression from the first dose. Its longer half-life (~7–8 hours vs ~1–2 hours for PPIs) and food-independent dosing are additional differentiators. For H. pylori eradication, vonoprazan-based triple and dual therapy demonstrated superiority over lansoprazole-based triple therapy, particularly in patients with clarithromycin-resistant strains.
PPI-refractory erosive esophagitis — Evidence quality: Moderate. Small studies suggest that switching from a PPI to vonoprazan may improve acid control and mucosal healing in patients who have failed standard PPI therapy.
NSAID-associated gastroprotection — Evidence quality: Moderate (Japan data). Vonoprazan is approved in Japan for prevention of low-dose aspirin and NSAID-induced ulcers at 10 mg daily, but this indication is not FDA-approved in the US.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Erosive esophagitis — healing | 20 mg once daily | 20 mg once daily | 20 mg/day | 8 weeks Take with or without food; swallow whole |
| Healed EE — maintenance and heartburn relief | 10 mg once daily | 10 mg once daily | 10 mg/day | Up to 6 months |
| Non-erosive GERD — heartburn relief | 10 mg once daily | 10 mg once daily | 10 mg/day | 4 weeks |
| H. pylori — triple therapy | 20 mg twice daily | 20 mg twice daily | 40 mg/day | With amoxicillin 1 g BID + clarithromycin 500 mg BID, morning and evening (12 h apart), for 14 days |
| H. pylori — dual therapy | 20 mg twice daily | 20 mg twice daily | 40 mg/day | With amoxicillin 1 g three times daily (morning, midday, evening), for 14 days Dual therapy avoids clarithromycin; amoxicillin TID distinguishes this from triple therapy |
Renal Impairment Dosing
| Clinical Scenario | eGFR ≥30 mL/min | eGFR <30 mL/min | Notes |
|---|---|---|---|
| EE healing | 20 mg QD | 10 mg QD | Dose reduced in severe renal impairment |
| EE maintenance / Non-erosive GERD | 10 mg QD | 10 mg QD | No adjustment |
| H. pylori (triple or dual) | 20 mg BID | Not recommended | Also refer to amoxicillin/clarithromycin renal dosing |
Hepatic Impairment Dosing
| Clinical Scenario | Child-Pugh A | Child-Pugh B | Child-Pugh C |
|---|---|---|---|
| EE healing | 20 mg QD | 10 mg QD | 10 mg QD |
| EE maintenance / Non-erosive GERD | 10 mg QD | 10 mg QD | 10 mg QD |
| H. pylori (triple or dual) | 20 mg BID | Not recommended | Not recommended |
Vonoprazan can be taken with or without food and does not require pre-meal timing. Unlike PPIs, its acid-suppressive effect is clinically meaningful from the first dose — reaching approximately 63% pH >4 time on day 1, increasing to ~85% by day 7 at 20 mg. Tablets must be swallowed whole (no crushing or chewing). For H. pylori missed doses, take within 4 hours; for EE/GERD, take within 12 hours. Clarithromycin co-administration increases vonoprazan AUC by approximately 58% via CYP3A4 inhibition, but no dose adjustment is needed.
Pharmacology
Mechanism of Action
Vonoprazan is a potassium-competitive acid blocker (P-CAB) that suppresses gastric acid secretion by inhibiting the H+/K+-ATPase in a potassium-competitive manner at the secretory surface of parietal cells. This mechanism differs fundamentally from PPIs in several clinically important ways. First, vonoprazan does not require acid-catalysed activation — it directly inhibits the proton pump as the parent compound, whereas PPIs must be converted to a reactive sulfenamide in an acidic environment. Second, vonoprazan binds the proton pump reversibly and noncovalently, in contrast to the irreversible covalent binding of PPIs. Third, vonoprazan inhibits both active (acid-secreting) and resting proton pumps, while PPIs can only bind pumps in the active conformation. Its high pKa of 9.6 promotes selective accumulation in the acidic canalicular space of parietal cells, and its acid stability means it does not degrade in the stomach. These properties result in faster onset of acid suppression (within 2–3 hours of a single dose), more complete and sustained pH control, and less dependence on meal timing or CYP2C19 genotype.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; Tmax 1.5–2 h; food has minimal effect on exposure; acid-stable (no enteric coating needed); linear PK 10–40 mg | Can be dosed without regard to meals; provides rapid onset of acid suppression from first dose |
| Distribution | ~80% plasma protein bound; Vd ~1,050 L (apparent); high pKa (9.6) concentrates drug in acidic parietal cell canaliculi; binds active and resting pumps | Extensive tissue distribution; selective accumulation at site of action explains prolonged pharmacological effect despite moderate plasma half-life |
| Metabolism | Extensive hepatic: mainly CYP3A4; also CYP2B6, CYP2C19, CYP2D6, and SULT2A1; all metabolites pharmacologically inactive | CYP2C19 genotype has minimal impact on exposure (~15–29%); vonoprazan is a CYP2C19 inhibitor and weak CYP3A inhibitor; clarithromycin co-administration increases vonoprazan AUC ~58% |
| Elimination | t½ ~7–8 h; ~59% urinary excretion as metabolites, ~8% unchanged in urine; steady state by day 3–4; minimal accumulation (accumulation index <1.2) | Substantially longer half-life than PPIs (~1–2 h); allows once- or twice-daily dosing; dose adjustment for severe renal (eGFR <30) and moderate-severe hepatic impairment |
Side Effects
No individual adverse reaction exceeded 10% in vonoprazan-treated patients across any indication. In the H. pylori lansoprazole comparator arm, diarrhoea reached 10%.
EE Healing (N=514 vonoprazan 20 mg vs N=510 lansoprazole 30 mg; ≥2%)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Gastritis | 3% (vs 2% lansoprazole) | Grouped term; slightly above comparator |
| Diarrhoea | 2% (vs 3% lansoprazole) | Actually lower than comparator in this trial |
| Abdominal distension | 2% (vs 1%) | Twice the comparator rate |
| Abdominal pain | 2% (vs 1%) | Grouped term |
| Nausea | 2% (vs 1%) | Mild in most cases |
EE Maintenance (N=296 vonoprazan 10 mg vs N=297 lansoprazole 15 mg; ≥3%)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Gastritis | 6% (vs 3% lansoprazole) | Double the comparator rate; most common adverse reaction in maintenance phase |
| Abdominal pain | 4% (vs 2%) | Grouped term |
| Dyspepsia | 4% (vs 3%) | Marginally above comparator |
| Hypertension | 3% (vs 2%) | Grouped term; monitor blood pressure in long-term use |
| Urinary tract infection | 3% (vs 2%) | Slightly above comparator |
Non-Erosive GERD (N=259 vonoprazan 10 mg vs N=256 placebo; ≥2%)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Abdominal pain | 2% (vs 2% placebo) | No difference from placebo |
| Constipation | 2% (vs 1%) | Modest increase over placebo |
| Diarrhoea | 2% (vs 1%) | Modest increase over placebo |
| Nausea | 2% (vs <1%) | Higher than placebo |
| Urinary tract infection | 2% (vs 1%) | Modest increase over placebo |
H. pylori Triple Therapy (N=346; ≥2%) and Dual Therapy (N=348; ≥2%)
| Adverse Effect | Triple | Dual | Clinical Note |
|---|---|---|---|
| Diarrhoea | 4% | 5% | Notably lower than LAC comparator (10%) |
| Dysgeusia | 5% | 1% | Driven by clarithromycin; nearly absent in dual therapy |
| Vulvovaginal candidiasis | 3% | 2% | Antibiotic-related; higher than LAC (1%) |
| Abdominal pain | 2% | 3% | Similar to LAC (3%) |
| Headache | 3% | 1% | Higher in triple than dual or LAC |
| Hypertension | 2% | 1% | Grouped term |
| Nasopharyngitis | <1% | 2% | More common in dual therapy |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Acute tubulointerstitial nephritis | Rare (reported in trials) | Any point | Discontinue vonoprazan; evaluate renal function |
| Clostridioides difficile-associated diarrhoea | Rare (post-marketing, with antibacterials) | Days to months | Stool testing; discontinue; targeted antibiotic therapy |
| Bone fracture (including osteoporosis-related) | Reported in trials (≤1%) | With long-term use | Use shortest duration; manage per guidelines |
| Severe cutaneous reactions (SJS, TEN) | Very rare (post-marketing) | Days to weeks | Immediate discontinuation; emergency care |
| Hepatic injury / hepatic failure / jaundice | Very rare (post-marketing) | Variable | Monitor liver function; discontinue if suspected |
| Hypomagnesaemia / hypocalcaemia / hypokalaemia | Rare (post-marketing) | With prolonged use | Check electrolytes; supplement; consider discontinuation |
| Vitamin B12 deficiency | Rare (post-marketing) | With long-term use | Monitor B12; supplement if deficient |
| Anaphylactic shock | Very rare (post-marketing) | Any time | Emergency care; permanent discontinuation |
| Fundic gland polyps | Reported in trials and post-marketing | With long-term use >1 year | Usually asymptomatic; use shortest treatment duration |
Gastritis was the most common adverse reaction in the EE maintenance phase (6% vs 3% lansoprazole). This finding is consistent with the pharmacological effect of profound acid suppression, which can lead to reactive changes in gastric mucosa including hypergastrinaemia-induced ECL cell hyperplasia. The clinical significance in the context of up to 6 months of therapy requires ongoing assessment.
Drug Interactions
Vonoprazan is a CYP3A substrate, a CYP2C19 inhibitor, and a weak CYP3A inhibitor. These properties create clinically important interactions distinct from PPIs. Strong or moderate CYP3A4 inducers should be avoided as they may reduce vonoprazan efficacy. The CYP2C19 inhibitory effect is relevant for clopidogrel (may reduce its active metabolite) and CYP2C19 substrates like citalopram and cilostazol (may increase their exposure).
Monitoring
- Magnesium / CalciumBaseline and periodically
RoutineMonitor in patients on prolonged treatment, those taking digoxin, or those on drugs causing hypomagnesaemia (diuretics). Supplement as needed; consider discontinuation if hypocalcaemia is refractory. - Chromogranin AHold vonoprazan ≥4 weeks before testing
Trigger-basedVonoprazan requires a 4-week washout before CgA testing — longer than the 14-day PPI hold. Also hold ≥4 weeks before secretin stimulation testing. This reflects more potent and sustained acid suppression. - Vitamin B12If symptoms develop
Trigger-basedConsider workup if clinical symptoms of B12 deficiency appear during long-term therapy. - Renal FunctionBaseline; if symptoms develop
Trigger-basedAcute TIN has been reported in clinical trials. Assess baseline eGFR for dosing purposes (EE healing and H. pylori adjustments required for eGFR <30). - Liver FunctionBaseline; if symptoms develop
Trigger-basedHepatic injury and failure reported post-marketing. Assess baseline hepatic function for dosing purposes. Monitor for signs of hepatotoxicity. - Symptom Response4–8 weeks
RoutineAssess symptom resolution at end of treatment. Suboptimal response does not exclude gastric malignancy — consider endoscopy, especially in older adults.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to vonoprazan or any component (reactions include anaphylactic shock)
- Concomitant use with rilpivirine-containing products
Relative Contraindications (Specialist Input Recommended)
- H. pylori treatment in moderate-severe hepatic impairment (Child-Pugh B/C) — vonoprazan not recommended for this indication
- H. pylori treatment in severe renal impairment (eGFR <30) — vonoprazan not recommended
- Concomitant strong/moderate CYP3A4 inducers — may reduce vonoprazan efficacy; avoid
Use with Caution
- Moderate-severe hepatic impairment (EE healing) — reduce dose to 10 mg daily
- Severe renal impairment (EE healing) — reduce dose to 10 mg daily
- Pregnancy — insufficient human data; animal studies showed fetal effects at supratherapeutic doses
- Lactation — breastfeeding not recommended; liver injury observed in nursing rat pups at clinically relevant exposures
- Paediatric patients — safety and effectiveness not established
- Patients on clopidogrel — vonoprazan is a CYP2C19 inhibitor and may reduce clopidogrel activation
- Long-term use — risks of bone fracture, fundic gland polyps, B12 deficiency, hypomagnesaemia
In a pre- and postnatal development study, liver discoloration associated with necrosis, fibrosis, and haemorrhage occurred in offspring of rats administered vonoprazan during gestation and lactation. Mechanistic studies demonstrated the effect was attributable to exposure during lactation. Patients should not breastfeed during treatment with vonoprazan.
Patient Counselling
Purpose of Therapy
Vonoprazan is a new type of acid-reducing medication that works differently from older medications like omeprazole. It is used to heal damage caused by stomach acid in the oesophagus, to relieve heartburn, and to treat H. pylori stomach infections.
How to Take
Take vonoprazan with or without food — meal timing does not matter. Swallow the tablet whole; do not crush or chew. For H. pylori treatment, take the full 14-day course exactly as directed with the prescribed antibiotics, even if you feel better.
Sources
- VOQUEZNA (vonoprazan) tablets prescribing information. Phathom Pharmaceuticals, Inc. NDA 218710. Revised 7/2024. accessdata.fda.govCurrent FDA-approved PI for single-agent vonoprazan — primary source for all GERD/EE indications, dosing (including renal/hepatic adjustments), adverse reactions Tables 5–8, drug interactions, and PK data.
- VOQUEZNA TRIPLE PAK / DUAL PAK prescribing information. Phathom Pharmaceuticals, Inc. NDA 215152/215153. Revised 2025. accessdata.fda.govCo-packaged product PI for H. pylori indications; source for eradication-specific adverse reactions, 14-day regimen dosing, and clarithromycin interaction data.
- FDA approval letter for VOQUEZNA (vonoprazan) NDA 218710, July 17, 2024. accessdata.fda.govApproval letter confirming single-agent vonoprazan approval for EE, EE maintenance, non-erosive GERD, and expanded H. pylori indications.
- Laine L, Lu Y, Engstrom A, et al. Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis: a randomized trial. Gastroenterology. 2023;164(1):61-71. doi:10.1053/j.gastro.2022.09.041PHALCON-EE: pivotal Phase 3 trial demonstrating non-inferiority of vonoprazan to lansoprazole for EE healing and superiority for LA grade C/D healing.
- Chey WD, Mégraud F, Laine L, et al. Vonoprazan triple and dual therapy for Helicobacter pylori infection in the United States and Europe: randomized clinical trial. Gastroenterology. 2022;163(4):1012-1022. doi:10.1053/j.gastro.2022.06.055PHALCON-HP: Phase 3 trial showing vonoprazan triple and dual therapy superiority over LAC for H. pylori eradication, especially in clarithromycin-resistant strains.
- Katz PO, Dunbar KB, Schnoll-Sussman FH, et al. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Am J Gastroenterol. 2022;117(1):27-56. doi:10.14309/ajg.0000000000001538Current GERD guideline; published before vonoprazan US approval but provides the therapeutic framework for EE management.
- Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017;112(2):212-239. doi:10.1038/ajg.2016.563ACG H. pylori guideline; vonoprazan-based regimens are expected to be incorporated into future guideline updates.
- Oshima T, Miwa H. Potent potassium-competitive acid blockers: a new era for the treatment of acid-related diseases. J Neurogastroenterol Motil. 2018;24(3):334-344. doi:10.5056/jnm18029Comprehensive review of P-CAB pharmacology, contrasting reversible K+-competitive inhibition with irreversible PPI binding.
- Graham DY, Dore MP. Update on the use of vonoprazan: a competitive acid blocker. Gastroenterology. 2018;154(3):462-466. doi:10.1053/j.gastro.2018.01.018Expert perspective positioning vonoprazan relative to PPIs, including relative acid-suppressive potency comparisons.
- Echizen H. The first-in-class potassium-competitive acid blocker, vonoprazan fumarate: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet. 2016;55(4):409-418. doi:10.1007/s40262-015-0326-7Key PK review: t½ ~7.7 h, Tmax 1.5–2 h, protein binding 80%, Vd 1050 L, CYP3A4 as primary metabolic pathway, and minimal CYP2C19 genotype effect.
- Frelinger AL 3rd, Lee RD, Engstrom A, et al. The effect of food on the pharmacokinetics of vonoprazan. Clin Pharmacol Drug Dev. 2022;11(8):915-924. doi:10.1002/cpdd.1090Food-effect study confirming minimal impact on vonoprazan bioavailability, supporting food-independent dosing.
- VA Pharmacy Benefits Management. Vonoprazan (VOQUEZNA) in Erosive Esophagitis — National Drug Monograph, May 2024. va.govVA comprehensive monograph providing independent clinical appraisal including GRADE evidence ratings for EE healing and maintenance.