SAFETY ALERT: FDA Warns of C. Difficile-Associated Diarrhea Risk with Proton Pump Inhibitors

The FDA has issued a warning that the use of proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD). Healthcare professionals are advised to consider a diagnosis of CDAD for patients taking PPIs who develop diarrhea including symptoms of abdominal pain and fever that does not improve. The FDA is working with manufacturers of PPIs to include information in the drug labels about the increased risk of CDAD. The agency is also reviewing the risk of CDAD with histamine H2 receptor blockers.

The FDA is reporting this potential risk after reviewing reports from the FDA's Adverse Event Reporting System (AERS) and the medical literature for cases of CDAD in patients undergoing treatment with PPIs. Many of the adverse event reports involved patients who were elderly, had chronic and/or concomitant underlying medical conditions, or were taking broad spectrum antibiotics that could have predisposed them to developing CDAD. Although these factors could have increased their risk of CDAD, the role of PPI use cannot be definitively ruled out in these reviewed reports. Patients who have one or more of these risk factors may have serious outcomes from CDAD with concomitant PPI use.

FDA also reviewed a total of 28 observational studies described in 26 publications. Twenty-three of the studies showed a higher risk of C. difficile infection or disease, including CDAD, associated with PPI exposure compared to no PPI exposure. Although the strength of the association varied widely from study to study, most studies found that the risk of C. difficile infection or disease, including CDAD, ranged from 1.4 to 2.75 times higher among patients with PPI exposure compared to those without PPI exposure. In the five studies that provided information on clinical outcomes, colectomies, and rarely deaths, were reported in some patients

The published studies varied in their ability to assess the association between C. difficile infection or CDAD and prior PPI use. There were limited data on the relationship between the risk of C. difficile infection or CDAD and PPI dose and duration of use. There also was little information on the use of OTC PPIs in community settings in these studies. Nevertheless, the weight of evidence suggests a positive association between the use of PPIs and C. difficile infection and disease, including CDAD.

PPIs are available by prescription for the treatment of gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus, and over-the-counter (OTC) for the treatment of frequent heartburn. They include AcipHex (rabeprazole sodium; Janssen), Dexilant (dexlansoprazole; Takeda), Nexium (esomeprazole magnesium; AstraZeneca), Prevacid (Takeda) and OTC Prevacid 24HR (lansoprazole; Novartis Consumer Health), Prilosec (AstraZeneca) and Prilosec OTC (omeprazole; Procter & Gamble), Protonix (pantoprazole sodium; Pfizer), and Zegerid (Santarus) and Zegerid OTC (omeprazole and sodium bicarbonate; Merck). Vimovo (esomeprazole magnesium and naproxen; AstraZeneca) is indicated for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis: to improve symptoms and reduce risk of gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers.

For more information visit www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm290838.htm?source=govdelivery.