Many primary care providers rely on traditional proton pump inhibitors (PPIs), such as omeprazole and esomeprazole, or H2-receptor antagonists such as famotidine, for reflux management.¹ PPIs are effective for many patients, but they generally need to be taken 30 to 60 minutes before meals for best effect, and a substantial proportion of patients with suspected GERD do not achieve adequate symptom relief from acid suppression alone.^1,2 We offer evidence-based options tailored to the clinical situation.

Voquezna (vonoprazan)

A potassium-competitive acid blocker (PCAB) with a mechanism distinct from traditional PPIs. Unlike PPIs, vonoprazan does not require acid activation, does not require premeal dosing, begins raising intragastric pH within 2 to 3 hours, and maintains strong acid suppression over 24 hours.³ In phase 3 trials, vonoprazan improved heartburn as early as day 1 in nonerosive reflux disease and was superior to lansoprazole for healing and maintenance of healing of erosive esophagitis, with the greatest benefit in more severe disease.^4,5 Compared with several PPIs, PCABs also show less pharmacodynamic variability related to CYP2C19 status, and reduced drug interaction risk.⁶ Current expert guidance supports selective use when faster onset, no premeal dosing requirement, or persistent symptoms despite optimized PPI therapy are the main clinical issues.⁷

Pantoprazole

When a traditional PPI is appropriate, we favor pantoprazole over other options in the class. It has significantly fewer drug-drug interactions than omeprazole or esomeprazole because it’s metabolized through multiple pathways and doesn’t inhibit CYP2C19 or CYP3A4 as much as other PPIs. This makes it safer for patients on multiple medications, particularly antiplatelet agents like clopidogrel, and certain other medications ^8,9

Famotidine (H2 blocker)

H2 blockers are less potent than PPIs for healing erosive esophagitis and maintaining healing, but famotidine can still be useful for mild, intermittent, or breakthrough reflux symptoms.¹ Famotidine may be dosed once nightly or twice daily in prescription use, and OTC formulations can be used to relieve or prevent episodic heartburn.^10,11 Compared with PPIs, H2 blockers have shown less alteration of the gut microbiome in comparative studies and lower Clostridioides difficile risk in some comparative analyses, although the CDI data are largely observational and strongest in hospitalized stress-ulcer populations.^12,13 Famotidine has also been used as adjunctive therapy in chronic urticaria, but international guidelines note that evidence for H2-antihistamines such as famotidine is variable.¹⁴

Addressing Underlying Contributors

We also address underlying contributors to reflux rather than simply escalating acid suppression indefinitely.² This includes optimizing dose timing and adherence, reviewing evidence-based lifestyle measures such as weight loss when appropriate, avoiding meals within 2 to 3 hours of bedtime, and elevating the head of the bed for nocturnal symptoms.^1,2 When clinically indicated, we also evaluate for H. pylori rather than reflexively increasing long-term acid suppression without reassessing the diagnosis.^2,15

---

References

1. 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.0000000000001538
2. Yadlapati R, Gyawali CP, Pandolfino JE, et al. AGA Clinical Practice Update on the Personalized Approach to the Evaluation and Management of GERD: Expert Review. Clin Gastroenterol Hepatol. 2022;20(5):984-994.e1. doi:10.1016/j.cgh.2022.01.025
3. VOQUEZNA- vonoprazan fumarate tablet. DailyMed. Accessed April 16, 2026.
4. Laine L, Spechler S, Yadlapati R, et al. Vonoprazan Is Efficacious for Treatment of Heartburn in Non-Erosive Reflux Disease: A Randomized Trial. Clin Gastroenterol Hepatol. 2024;22(11):2211-2220.e10. doi:10.1016/j.cgh.2024.05.004
5. Laine L, DeVault K, Katz P, 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.2022.09.041
6. Lima JJ, Thomas CD, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. Clin Pharmacol Ther. 2021;109(6):1417-1423. doi:10.1002/cpt.2015
7. Patel A, Laine L, Moayyedi P, Wu J. AGA Clinical Practice Update on Integrating Potassium-Competitive Acid Blockers Into Clinical Practice: Expert Review. Gastroenterology. 2024;167(6):1228-1238. doi:10.1053/j.gastro.2024.06.038
8. CLOPIDOGREL BISULFATE tablet, film coated. DailyMed. Accessed April 16, 2026.
9. PANTOPRAZOLE SODIUM delayed-release tablet. DailyMed. Accessed April 16, 2026.
10. FAMOTIDINE tablet. DailyMed. Accessed April 16, 2026.
11. HEARTBURN RELIEF ORIGINAL STRENGTH- famotidine tablet. DailyMed. Accessed April 16, 2026.
12. Zhu J, Sun C, Li M, et al. Compared to Histamine-2 Receptor Antagonist, Proton Pump Inhibitor Induces Stronger Oral-to-Gut Microbial Transmission and Gut Microbiome Alterations: A Randomised Controlled Trial. Gut. 2024;73(7):1087-1097. doi:10.1136/gutjnl-2023-330168
13. Azab M, Doo L, Doo DH, et al. Comparison of the Hospital-Acquired Clostridium difficile Infection Risk of Using Proton Pump Inhibitors Versus Histamine-2 Receptor Antagonists for Prophylaxis and Treatment of Stress Ulcers: A Systematic Review and Meta-Analysis. Gut Liver. 2017;11(6):781-788. doi:10.5009/gnl16568
14. Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The International EAACI/GA²LEN/EuroGuiDerm/APAAACI Guideline for the Definition, Classification, Diagnosis, and Management of Urticaria. Allergy. 2022;77(3):734-766. doi:10.1111/all.15090
15. Chey WD, Howden CW, Moss SF, et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2024;119(9):1730-1753. doi:10.14309/ajg.0000000000002968