Curr Med Res Opin. 2015 Mar;31(3):407-20.

One-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled analyses of two 24-week randomized, double-blind trials and a follow-on extension.


Bello AE1, Grahn AY, Ball J, Kent JD, Holt RJ.
  • 1University of Illinois-Chicago, College of Medicine, and Illinois Bone and Joint Institute LLC , Glenview, IL , USA.




To evaluate the safety of the fixed combination of ibuprofen and famotidine compared with ibuprofen alone from two 24-week, multicenter, double-blind trials designed to evaluate the comparative incidence of endoscopically documented upper gastrointestinal ulcers and a 28-week double-blind extension study.


Safety was analyzed by pooling data from the two double-blind trials and the follow-on study. Safety was assessed by monitoring the incidence, causality, and severity of adverse events (AEs).


In the pivotal efficacy and safety trials, discontinuation rates due to any cause and dyspepsia were significantly lower for the ibuprofen/famotidine combination versus ibuprofen alone. Other than dyspepsia, gastrointestinal and cardiovascular AEs of special interest were similar. Events judged to be treatment related were significantly lower with the ibuprofen/famotidine combination (20.6% vs. 25%). In the safety extension population, there were no differences in the discontinuation rates and the reporting of AEs or serious AEs (SAEs) between the two groups. Gastrointestinal-related events were similar between the groups. Incidence of cardiovascular-related AEs of special interest were 11% (ibuprofen/famotidine) and 2% (ibuprofen) (p=0.06), possibly due to a higher number of rheumatoid arthritis patients in the combination group. Of these, 80% were reports of hypertension (8% ibuprofen/famotidine vs. 2% ibuprofen). Three cases of hypertension in the ibuprofen/famotidine group were considered treatment related. The probability of a cardiovascular event decreased during days 112-167 of treatment and remained low with continued treatment.


One-year safety data from two pivotal trials and a long-term extension study indicate that the ibuprofen/famotidine combination demonstrates a favorable gastrointestinal safety profile and more patients continued on therapy compared to ibuprofen alone. No new safety signals have been identified. These data offer additional evidence supporting a new therapeutic option to improve gastrointestinal safety and adherence for patients who require long-term ibuprofen.


Arthritis, rheumatoid; Cardiovascular; Famotidine; Gastrointestinal; Ibuprofen; Non-steroidal anti-inflammatory agents; Safety

PMID: 25516006



Approximately 25% of patients taking a non-steroidal anti-inflammatory drug (NSAID) for 3 to 6 months will develop a serious gastrointestinal (GI) adverse effect observable by endoscopy and hence most regulatory agencies require all NSAIDS to carry a “black box” warning to this effect.1,2 Symptomatic GI ulcers and complications vary among NSAID users but range from 2.7% to 4.5%.3-6 These adverse events are caused by direct and indirect actions from the NSAID’s reduction in prostaglandins that protect and maintain homeostasis in the GI tract. NSAID associated damage may occur in any patient but certain risk factors significantly increase the chances for a clinical event. These include a history of GI disease, older age, presence of H. pylori infection, alcohol consumption, male gender, concomitant use of corticosteroids, aspirin, and anticoagulation therapy, and prolonged and/or high dose use of NSAIDs.7


Studies of fixed combination NSAID/anti-secretory products’ gastroprotective efficacy indicate that some patients in need of anti-inflammatory doses of NSAID therapy (i.e., moderate to severe osteoarthritis and rheumatoid arthritis) but at high GI risk, seem to benefit equally to those with lesser GI risk.8-10 As an example, in controlled active comparison trials in OA patients greater than 60 years of age who received an ibuprofen/famotidine combination, as compared with an equal dose of ibuprofen alone, showed a significant reduction in the incidence of endoscopic upper GI ulcers.9 Likewise, overall safety analyses of these combination products in patients at high GI risk (concomitant anticoagulation, low dose aspirin, and older age) have shown comparability as compared with patients at lower risk.8-11 These data indicate in aggregate that patients at higher GI risk can be successfully managed with anti-inflammatory doses of NSAIDs with combination gastroprotective therapy. One caveat is that cardiovascular (CV) safety has not been sufficiently studied in this population of at-risk patients.12


Finally, topical NSAID therapy is another strategy to use in at-risk patients who require NSAID therapy. Studies indicate that in patients where topical therapy is warranted (i.e. knee OA) systemic exposure can be reduced by up to 93%.13 This reduced systemic exposure has been associated with significant reductions in major NSAID mediated adverse events, including those of CV origin.14



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  8. Bello AE, Kent JD, Holt RJ. Gastroprotective Efficacy and Safety of Single-Tablet Ibuprofen/Famotidine vs Ibuprofen in Older Persons. Phys Sportsmed 2015; Early Online: 1–7 DOI10.1080/00913847.2015.1066229.
  9. Bello AE, Kent JD, Grahn AY, et al. Risk of Upper Gastrointestinal Ulcers in Patients with Osteoarthritis Receiving Single-Tablet Ibuprofen/Famotidine versus Ibuprofen Alone: Pooled Efficacy and Safety Analyses of Two Randomized, Double-Blind, Comparison Trials. Postgrad Med 2014;126(4):82-91.
  10. Bello A, Kent J, Grahn A, et al. One-year open-label safety evaluation of the fixed combination of ibuprofen and famotidine with a prospective analysis of dyspepsia. Curr Med Res Opin 2015;31(3):397-405.
  11. Holt RJ, Fort JG, Grahn AY, et al. Onset and Durability of Pain Relief in Knee Osteoarthritis: Pooled Results From 2 Placebo Trials of Naproxen/Esomeprazole Combination and Celecoxib. Phys Sportsmed 2015; Early Online: 1–13. DOI: 10.1080/00913847.2015.1074852.
  12. Bello AE, Holt RJ. Cardiovascular Risk with Non-steroidal Anti-inflammatory Drugs: Clinical Implications. Invited commentary. Drug Saf 2014;37(11):897-902
  13. Holt RJ, Taiwo T, Kent JD. Bioequivalence of diclofenac sodium 2% and 1.5% topical solutions relative to oral diclofenac sodium in healthy volunteers. Postgrad Med 2015;127(6): 581–590.
  14. Roth SH, Fuller P. Diclofenac topical solution compared with oral diclofenac: a pooled safety analysis. J Pain Res 2011;4:159–67.




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