Evid Based Med 18:26-27 doi:10.1136/ebmed-2012-100711
  • Therapeutics
  • Randomised controlled trial

Single-tablet double-dose famotidine plus ibuprofen decreases endoscopic upper GI ulcers compared with ibuprofen alone

  1. Kentaro Sugano
  1. Department of Medicine, Jichi Medical University, Shimotsuke, Japan
  1. Correspondence to: Kentaro Sugano
    Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan; sugano{at}

Commentary on: [CrossRef][Medline]Google Scholar


Non-steroidal anti-inflammatory drugs (NSAID) are widely prescribed worldwide. However, NSAID use frequently accompanies gastrointestinal (GI) injury including complications such as bleeding and perforation. Therefore co-therapy with gastroprotective drugs especially for those at risk has been advocated in current guidelines1 in which proton-pump inhibitors (PPI) and misoprostol are recommended to reduce NSAID-induced gastroduodenal ulcers. Another approach is to use cyclooxygenase-2 (COX-2) specific inhibitors.1 The role of histamine-2 receptor antagonists (H2RAs), however, remains uncertain in this regard. The only H2RA that showed significant protective effects is famotidine, but a double-dose is required for reducing gastric ulcers2 and the rate of peptic ulcer occurrence was high in one study.3


The efficacy and safety of single-tablet ibuprofen/double-dose famotidine compared with ibuprofen alone in reducing gastroduodenal ulcers was tested in two double-blind randomised trials (REDUCE-1 and -2) for 24 weeks.4 Because of the dosing schedule of ibuprofen (800 mg three times per day), famotidine was also given three times a day (26.6 mg/each). The study included subjects who required NSAIDs for 6 months or more, who were negative for Helicobacter pylori, had no active ulcers at enrolment, and no prior history of ulcer complications. Those taking low-dose aspirin (LDA), ≤325 mg/day and/or anticoagulants were included. Although different endpoints were defined in the individual trials, gastroduodenal ulcers developed during 24 weeks were the primary endpoint in the pooled analysis. Comparison of the proportion of patients with dyspeptic symptoms between the two groups was also done.


Prespecified pooled analysis of the two trials demonstrated significantly fewer gastric (12.5% vs 20.7%) and duodenal ulcers (1.1% vs 5.1%) with single-tablet ibuprofen/high-dose famotidine versus ibuprofen alone. Proportional hazard analysis of multiple risk factors showed the RR for upper GI ulcers with single-tablet ibuprofen/high-dose famotidine versus ibuprofen alone was 0.46 (95% CI 0.34 to 0.61). In the subgroup analysis, the protective effect of single-tablet ibuprofen/high-dose famotidine in LDA co-users was not compromised. However, no benefit in reducing dyspeptic symptoms with ibuprofen/high-dose famotidine, as compared with ibuprofen alone, was shown.


Despite recommendations of gastroprotective co-therapy for at risk patients, both adherence of doctors and compliance of patients has been disappointingly low.5 ,6 Therefore, single-tablet formulations (combinations of diclofenac/misoprostol, naproxen/esomeprazole and ibuprofen/famotidine) have been launched in the hope of improving safety.

The REDUCE trials data clearly demonstrated the benefit of single-tablet high-dose famotidine/ibuprofen in reducing upper GI ulcers. However, the rate of ulcer development in these trials was almost double of that seen with single-tablet esomeprazole (20 mg)/enteric coated naproxen (500 mg) twice daily.7 Co-administration of LDA did not influence the protective effects of the esomeprazole/naproxen combination. Symptomatic scores and tolerability in the PPI/naproxen combination as compared with naproxen alone were better. Moreover, the price of single-tablet naproxen/esomeprazole is lower than that of double-dose famotidine/ibuprofen combination in the USA. Comparable long-term data on a misoprostol/diclofenac combination are not available, but its use would be limited due to increased GI adverse events.8 Although more data are needed to judge the superiority of these single-tablet regimens in reducing ulcers and their complications in clinical practice, the single-tablet esomeprazole/naproxen combination would be the preference at the moment, considering the magnitude of risk reduction, simpler dosing schedule, cost advantage (at least currently, in the USA) and symptomatic benefits.


  • Competing interests KS has received research grants from Takeda Pharmaceuticals, Eisai Pharmaceuticals, Astellas Pharmaceuticals and Astra-Zeneca Japan. He is also a consultant for Takeda Pharmaceuticals and Astra-Zeneca Japan and has received lecture fees from Takeda Pharmaceuticals.


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