Digestive Health Associates

Southwest Endoscopy Center

Proton Pump Inhibitors (PPIs)

Proton pump inhibitors, medications which reduce gastric (stomach) acid secretion, include the following commonly prescribed medications.  The most inexpensive over-the-counter nonprescription forms of these medications are shown in bold below.  Omeprazole, which is the oldest drug in this class, has been in widespread use for more than 25 years.

  • Omeprazole 20 mg (Prilosec® OTC and multiple generic store brands)
    • available without prescription
    • least expensive treatment option
  • Prilosec® (omeprazole)
  • Omeprazole
    • available as generic
  • Prevacid® (lansoprazole)
  • Lansoprazole
    • available as generic
  • Prevacid 24H® (lansoprazole)
    • approved by FDA for nonprescription sale in May 2009
  • Aciphex® (rabeprazole)
  • Protonix® (pantoprazole)
    • available as generic
  • Nexium® (esomeprazole)
  • NEXIUM® 24HR
    • Approved by FDA for nonprescription sale in March 2014
  • Dexilant® formerly Kapidex® (dexlansoprazole)
PPIs are frequently recommended for the acute and long-term management of gastroesophageal reflux disease (GERD) and in the long-term prevention of gastroduodenal ulcer disease secondary to nonsteroidal anti-inflammatory drugs (NSAIDs).  They are also commonly used in the acute management of peptic ulcer disease and in the treatment of Helicobacter pylori infections of the stomach.  These drugs are generally quite safe and well tolerated, effective in controlling symptoms, and effective in healing and keeping healed the acid-related inflammation (such as erosive esophagitis) that can lead to serious complications.  They vary widely in cost.  Serious side effects are unusual, though as with any medication, PPIs should be used on a long-term basis only when the benefits of treatment exceed the risks.  In many cases a determination of the necessity of long-term treatment may require trials of withdrawal from the drug, in order to assess potential symptom relapse and its effect on your health-related quality of life.  In other cases the risks of a complication of drug withdrawal may exceed the risks of continued treatment.  Decision-making about the best course of action in your case should made in consultation with your physician.
The Choosing Wisely Campaign of the American Board of Internal Medicine Foundation and American Gastroenterological Association, announced in April 2012, established the following statement as the first item of "Five Things Physicians and Patients Should Discuss."
For pharmacological treatment of patients with gastroesophageal reflux disease (GERD), long-term acid suppression therapy (proton pump inhibitors or histamine2 receptor antagonists) should be titrated to the lowest effective dose needed to achieve therapeutic goals.

Risks of Long-Term PPI Use
The information on this page is periodically updated (most recently in January 2017).

Based on a record of more than 25 years of world-wide use, the following safety concerns have been identified as potentially associated (which does not mean that the potential side-effect has been proven or that PPI use is causative of the side-effect) with PPI use :

  • Possible increased risk for Clostridium difficile and other intestinal infections and small intestinal bacterial overgrowth  
  • Possible increased risk for pneumonia 
  • Possible increased risk for impaired vitamin B12 absorption 
  • Possible increased risk for low blood magnesium level, due to impaired absorption 
  • Possible increased risk for low iron levels, due to impaired absorption 
  • Possible increased risk for hip, wrist and spine fractures, and osteoporosis, suspected to be due to impaired calcium absorption
  • Possible increased risk for heart disease, such as heart attack (coronary artery disease)
  • Possible increased risk for acute or chronic kidney disease
  • Possible increased risk for dementia, including Alzheimer disease
  • Possible increased risk for atrophic gastritis
  • Possible increased risk for stroke
  • Possible increased risk for drug interactions, particularly between omeprazole/esomeprazole and clopidogrel (Plavix) and PPIs and high-dose (particularly IV) methotrexate

Several studies have recently suggested an increased risk for hip or other fractures in association with the chronic use of these medications.  The FDA issued a change to drug label for all PPI medication on May 25, 2010, as discussed in these links:

Proton Pump Inhibitors (PPI): Class Labeling Change
including Nexium, Dexilant, Prilosec, Zegerid, Prevacid, Protonix, Aciphex, Vimovo, Prilosec OTC, Zegerid OTC, and Prevacid 24HR

FDA Consumer Update:  Possible Increased Risk of Bone Fractures With Certain Antacid Drugs

In response to this FDA action the American College of Gastroenterology issued this statement:
The FDA in its press statement today acknowledged that "based on the available data, at this time it is not clear if the use of proton pump inhibitors is the cause of the increased risk of fractures seen in some epidemiologic studies."  The FDA cites reports which are observational case-control studies with overall low hazard ratios and inherent bias potential, and the associations found in those studies were not supported by more recent reports. Clearly, the current science reflects uncertainty about the magnitude of the possible risk of bone fractures in patients using PPIs. The College urges patients not to stop PPIs without consulting a physician and notes that frequent, severe, and/or longstanding heartburn can be serious. 

A helpful study regarding this issue, published in the British Medical Journal in 2012, measured the fracture risk in 80,000 women and reported a 35% increase in fracture risk over 8 years in those who used PPIs compared to those who did not.  The risk was 50% higher in PPI users who also smoked.  This magnitude of risk can be expressed in the chance of fracture per 1000 person-years (meaning 1000 women followed for 1 year, or 100 women followed for 10 years).  The fracture risk in women not using PPIs was 1.5 per 1000 person-years.  In those using PPIs the risk increased to 2 per 1000 person-years.

Until more data are available, some physicians may recommend the use of calcium with vitamin D, particularly in the form of calcium citrate (Citracal®) in patients needing to take these medications long term.

Infections and Malabsorption of Nutrients

Other risks associated with the use of PPIs may include an increased risk for certain infections (community-acquired pneumonia, Clostridium difficile infection, infectious gastroenteritis), small intestinal bacterial overgrowth (SIBO) and effects related to chronic low stomach acid and its effects on the absorption of some nutrients (particularly vitamin B12 and iron) and changes in gut hormones such as gastrin.
This is the most recently raised concern.  Read the American College of Gastroenterology's statement.
Interactions with Other Medication (particularly Plavix®, or clopidogrel)

Recent studies show that combining a PPI with the anti-platelet drug Plavix® (clopidogrel) may decrease the effectiveness of the anti-platelet drug in some patients, though the clinical effect of this interaction appears to be minimal, based on the most current information.

When first reported, the potential for PPIs to reduce anti-platelet drug effectiveness concerned physicians because of the possibility of an associated increase in the risk of clot related events such as stroke, recurrent heart attack or clot formation within a coronary stent.  Patients for whom both PPI therapy and anti-platelet treatment with Plavix (clopidogrel) is indicated may have been asked to take their medication at different times of day (to decrease the potential for an adverse drug-drug interaction), or to switch to a different PPI, or to discontinue PPI therapy (often substituting a less potent type of acid inhibiting medication known as an H2-blocker), based on the estimated relative risks in their own case.  H2-blockers, also known as H2-antagonists, include the following medications, which are available in prescription and nonprescription strengths:  Tagamet® (cimetidine), Zantac® (ranitidine), Pepcid® (famotidine) and Axid® (nizatadine). 

Specialists in the fields of gastroenterology and cardiology have been monitoring research developments in this area closely.  In November of 2008 the American College of Gastroenterology (ACG), American Heart Association (AGA) and the American College of Cardiology (ACC) issued a joint statement after evaluating data presented at the ACC Meeting. At the time, these groups interpreted the strength of evidence in the available studies of PPIs and Plavix as being insufficient to cause a change in clinical practice.  The AHA/ACC and the American College of Gastroenterology recommended that patients who were taking these medications should not change their medication regimen unless advised by their health care provider. 

Since then, there has been 
evidence published suggesting that the interaction between Plavix® (clopidogrel)  and PPIs may be less of a problem, or may not occur, with the PPI Protonix® (pantoprazole), which is not metabolized through the P450 2C19 pathway.  A study presented in preliminary form on May 6, 2009 to the Society for Cardiovascular Angiography and Interventions (SCAI) however did not suggest that patients taking Protonix® (pantoprazole) are protected from this potential adverse drug interaction.  The 
SCAI statement, recommended that PPIs be avoided in patients who have recently been treated with coronary artery stents and are at high risk of cardiac complications, such as stent thrombosis (clot formation within the stent).

A study presented at the European Society of Cardiology Congress meeting on August 31, 2009, and published simultaneously in the Lancet, showed that the clinical effectiveness of antiplatelet therapy was not adversely affected by PPIs.

On November 17, 2009 the FDA issued a warning and required a label change for clopidogrel in a press conference at the American Heart Association meetings.  This action was taken on the basis of unpublished data. 

FDA Public Health Advisory:  Updated Safety Information about a drug interaction between Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole (marketed as Prilosec and Prilosec OTC)

Patients taking both Plavix® (clopidogrel) and a PPI should contact their physician for advice, particularly if they have been treated with a coronary stent during the last 6-12 months.  Certain types of stent (drug eluting stents) may carry a relatively higher risk for clot formation, requiring special consideration.  In some cases consultation between your primary care provider, cardiologist and gastroenterologist may be needed.

Low Blood Magnesium (hypomagnesemia)
The FDA posted a safety information report on March 2, 2011 recommending that healthcare professionals consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia.

Consumer reports has published a useful cost comparison for your review.  The nonprescription over-the-counter products (Prilosec® OTC and generic equivalents) represent the most cost effective option for most patients.