Drug Profile

Esomeprazole (NEXIUM), lansoprazole (PREVACID), omeprazole (PRILOSEC), pantoprazole (PROTONIX) and rabeprazole (ACIPHEX) are close chemical relatives in a family of ulcer drugs known as proton pump inhibitors (PPIs). Public Citizen lists them all as Limited Use drugs (offer limited benefits or benefit certain people or conditions).

These drugs are approved for short-term treatment of gastroesophageal reflux disease (GERD), and all of them but pantoprazole are also approved for duodenal and stomach ulcers that are resistant to treatment with antacids and histamine2-blockers. In addition, all PPIs except pantoprazole are approved for use in combination with antibiotics to treat ulcer disease caused by the bacterium Helicobacter pylori (H. pylori; see "Combination Treatments for Helicobacter Pylori Infection").

All five drugs are indicated for the treatment of Zollinger-Ellison syndrome, a rare hormonal disorder in which a stomach tumor causes excessive stomach acid production. The PPIs do not alter the course of this syndrome.

PPIs completely inhibit the secretion of stomach acid, whereas histamine2-blockers, such as cimetidine (TAGAMET), partially prevent production of the acid. Histamine2-blockers relieve heartburn pain more quickly than do PPIs.[2]

Treatment of ulcers takes up to six weeks; for Zollinger-Ellison syndrome, treatment time is indefinite. To maintain effectiveness in treating Zollinger-Ellison syndrome, the dose may need to be increased annually.[3] Patients who do not have H. pylori infection and who have increased acid secretion after discontinuing a PPI may require long-term use of these drugs.[4]

Doctors frequently overprescribe PPIs; for many people, these drugs are prescribed unnecessarily, putting patients at unnecessary risk of adverse effects. See our Worst Pills, Best Pills News articles from March 2008 and November 2011 for more information concerning the overuse of PPIs.

Patients who have been taking omeprazole since it was approved in 1989 have actually been receiving esomeprazole with each dose. Like many drugs, omeprazole is a mixture of two forms that are chemically identical mirror images of each other. These mirror images are called optical isomers, and esomeprazole is one of the two that make up omeprazole. Esomeprazole and omeprazole are both produced by the same company: AstraZeneca Pharmaceuticals.

Use in children

The drug product label for omeprazole states that, in patients younger than one year, the safety and effectiveness of the drug in the treatment of gastroesophageal reflux disease (GERD) and other pediatric uses have not been established.[5]

The use of PPIs to treat acid reflux symptoms in infants is at an all-time high. These drugs present serious safety risks to adults and young children, and the staggering increase in PPI use comes despite the fact that, until 2011, no drug from this class had been approved by the Food and Drug Administration (FDA) for use in children younger than one year.

In 2011, the FDA's approval of esomeprazole for the treatment of erosive esophagitis in children from one month to one year of age represented the first — and, so far, only — approval of a PPI for any indication in children younger than one year. The approval was based not on a clinical study conducted in infants for this indication, but rather on questionably inferring safety and effectiveness from studies in adults and children older than one year. The only randomized trial evaluating esomeprazole's effectiveness in infants showed the drug to be no more effective than a placebo. To this day, no PPI has been shown to be effective for treating GERD in infants.[6]

Rabeprazole is also approved for the short-term treatment of symptomatic GERD in patients 12 years of age and older and for short-term treatment of GERD in children one to 11 years of age.[7]

Adverse effects

Relapse of acid reflux is common.

Long-term acid suppression may lead to intestinal infections.[8] It is uncertain whether long-term suppression of stomach acid may also cause stomach cancer.[9],[10] After long-term treatment, vitamin B12 stores may be depleted in strict vegetarians and the elderly; vitamin B12 levels should be monitored in these patients.[8],[11]

A type of kidney inflammation called interstitial nephritis has been associated with omeprazole since 2000. This condition also has been reported with pantoprazole and lansoprazole.[12] Two studies published in 2016 suggest that PPI use may be associated with chronic kidney disease.[13],[14] Both studies showed that the risk of harm to the kidneys increased when PPIs were used at higher doses or for longer periods of time.

Published studies have suggested that there may be an increased risk of fractures in people taking PPIs, and the FDA has changed the product labels of these drugs to reflect this risk.

Low serum magnesium levels may occur if use of a PPI lasts longer than one year. Symptoms of low magnesium levels may include muscle spasm, irregular heartbeat and convulsions.

PPIs also are linked to Clostridium difficile-associated bacterial diarrhea, which can be fatal in some patients.

Lupus erythematosus is an autoimmune disease that causes the body's immune system to attack healthy tissue. Cutaneous (affecting the skin) and systemic (affecting multiple organs, which may include the skin, joints, kidneys, lungs, heart and nervous system) lupus erythematosus have been reported with use of PPIs.[15]

Severe adverse skin reactions, including allergic skin reactions, have rarely been associated with the use of PPIs.[16],[16]

Long-term use of PPIs may lead to stomach polyps, which only rarely develop into cancer.

In 2023, European Journal of Gastroenterology and Hepatology published an article showing that long-term use of omeprazole in patients 65 years and older was associated with an increased risk of gastric cancer.[3284]

Interactions with other drugs

A study published in 2008 investigating the effect of omeprazole on the action of clopidogrel (PLAVIX) plus aspirin therapy found that omeprazole significantly decreased the effect of the antiplatelet drug clopidogrel. This means that clopidogrel could be less effective in preventing strokes and heart attacks when used with omeprazole. Physicians and patients should be aware of this association because this drug combination is widely prescribed.[17]

A 2009 study in the Canadian Medical Association Journal found that people taking clopidogrel for a recent heart attack in combination with lansoprazole, omeprazole or rabeprazole — but not pantoprazole — had a 40% higher risk of having another heart attack compared with people who used only clopidogrel. This increased risk was probably caused by the PPI drugs blocking activation of clopidogrel.

Also, the FDA has stated that using cilostazol (a drug used to improve the flow of blood, listed on WorstPills.org as Do Not Use and available only in generic form) with omeprazole or esomeprazole is expected to increase the levels of cilostazol in the body.

Studies show...

Most studies do not show significant differences among the various PPIs for the treatment of GERD or duodenal ulcer.[18]

In 2016, JAMA Neurology published a study showing that regular PPI use was associated with an increased risk of new dementia.[19]

In 2021, the Journal of Clinical Pharmacy and Therapeutics published a study suggesting a link between the use of PPIs and an increased risk of developing or worsening of chronic obstructive pulmonary disease.[20]

Regulatory actions surrounding PPIs

2004: The "Warnings and Precautions" section of the pantoprazole product label was revised to include a drug interaction with warfarin (COUMADIN, JANTOVEN), a blood-thinning agent, which may lead to an increased risk of bleeding in patients taking the two drugs together.[21]

2007: The FDA added interstitial nephritis to the lansoprazole product label.[22]

The FDA also issued a communication concerning new safety data for omeprazole and esomeprazole. The results from two small, long-term clinical studies raised concerns that long-term use of these drugs may increase the risk of heart attack, heart failure and heart-related sudden death in those patients taking either of the drugs, compared with patients who had surgery to control their GERD. The FDA stated that health care providers should not change their prescribing practices and patients should not change their use of these products.[23]

In December, the FDA issued follow-up communications stating that the available data did not suggest an increased risk of heart problems for patients treated with these drugs.[24]

2009: The FDA issued a public advisory stating that it was aware of some reports that suggested that PPIs may make clopidogrel less effective in some patients. The makers of clopidogrel worked with the FDA to obtain additional information in relation to these reports.[25]

The FDA changed the clopidogrel drug label to warn that using certain classes of drugs that inhibit the activity of clopidogrel (such as omeprazole in the PPI family) should be discouraged in patients taking clopidogrel.[26]

In November, the FDA updated the product label of clopidogrel to state that administration of omeprazole and clopidogrel within 12 hours of each other reduces the effectiveness of clopidogrel. The warning also stated that this reduction in the effectiveness of clopidogrel was not observed with other drugs used to reduce stomach acid, except for cimetidine or antacids.[27]

2010: The FDA issued safety-labeling changes concerning the use of cilostazol in combination with esomeprazole or omeprazole. The updated information stated that using cilostazol with esomeprazole or omeprazole was expected to increase the levels of cilostazol in the body.[28]

The FDA also issued safety-labeling changes indicating that the use of PPIs can cause an increased risk of osteoporosis-related fractures of the hip, wrist or spine. This advisory was based on published studies suggesting that there may be an increased risk of fractures in people taking these medications. The FDA stated that the increased risk of fractures was noted in patients who were using PPIs for a year or longer and who were taking multiple daily doses.[29]

2011: In March, the FDA updated PPI product labels to warn of low serum magnesium levels when PPIs are taken for a long period of time — usually longer than one year.[30]

In May, another FDA advisory stated that low serum magnesium levels had been reported rarely in patients treated with PPIs for at least three months, but, in most cases, the condition was reported after a year of therapy. Most of these patients were treated for hypomagnesemia with magnesium replacement and discontinuation of the PPI. The FDA also stated that patients who are on prolonged treatment with PPIs or who take PPIs with medications such as digoxin (LANOXIN) or drugs that may cause hypomagnesemia (for example, diuretics) may need to have their magnesium levels monitored prior to initiation of PPI treatment and periodically thereafter.[30]

In August, Public Citizen petitioned the FDA to immediately add black box warnings and other safety information concerning several severe risks to the product labels of all PPIs on the market in the U.S. (esomeprazole, dexlansoprazole [DEXILANT], omeprazole, omeprazole and sodium bicarbonate [ZEGERID], lansoprazole, pantoprazole, rabeprazole, esomeprazole and naproxen [VIMOVO]; PRILOSEC OTC, ZEGERID OTC, PREVACID 24-HR; and all other generic counterparts).

We petitioned the FDA to require black box warnings on the labels of PPIs identifying the following risks related to use of these drugs: rebound acid hypersecretion, which results in dependence on these frequently overused drugs; fracture; C. difficile-associated diarrhea; and magnesium deficiency. We also petitioned the FDA to update the labels for all PPIs to include a description of interactions with clopidogrel, methotrexate (OTREXUP, RASUVO, TREXALL; a drug used for treating rheumatoid arthritis, certain cancers and other conditions) and mycophenolate mofetil (CELLCEPT; a drug used in organ transplantation); the risks of vitamin B12 deficiency and acute interstitial nephritis; and recommendations on length of treatment when used for GERD.

In addition, the petition stated that the serious nature of so many of these adverse reactions mandates the creation of an FDA-approved patient Medication Guide.

On Oct. 31, 2014, the FDA granted some of the actions requested in our petition and denied others. Specifically, the FDA agreed with and granted the following requests:

• In the labeling of all PPI products, the addition of information regarding the risk of C. difficile-associated diarrhea and the risk of drug-drug interactions between PPIs and mycophenolate mofetil (anti-transplant rejection drug) and methotrexate (for rheumatoid arthritis and other conditions);
• In the labeling of certain PPI products (omeprazole and esomeprazole), the addition of information regarding the risk of drug-drug interactions with clopidogrel;
• In the labeling of certain prescription PPI products, the addition of information regarding the risks of vitamin B12 deficiency and acute interstitial nephritis and certain information regarding treatment length for GERD;
• The issuance of Medication Guides for certain prescription PPI products regarding certain safety risks.

2012: In February, the FDA issued an advisory that PPIs may be associated with an increased risk of C. difficile-associated diarrhea. Patients who take a PPI and develop diarrhea that does not improve should be evaluated for a C. difficile infection.[31] The FDA required PPI manufacturers to include information about this risk in the drugs' labels.

2013: In April, Health Canada (the Canadian equivalent to the FDA) also issued a warning regarding the risk of fractures associated with the use of PPIs. This warning was similar to the FDA's 2010 safety-labeling changes.[32]

2018: The FDA approved updates to the drug product labels of PPIs to warn that long-term use of PPIs is associated with an increased risk of stomach polyps.[33]