Public Citizen petitions FDA to add several warnings to all proton pump inhibitors, including OTCs – which the agency previously determined do not pose the same level of risk as prescription versions.

“Currently labeling for PPIs is dangerously deficient,” and OTC labels in particular have “scant, if any, information regarding many of the risks,” the research-based advocacy group writes in an Aug. 23 petition.

The group asks FDA to add black box warnings to prescription PPIs, “and equivalent, prominent warnings for over-the-counter” products, about the increased risk of “potentially fatal” fractures, infection and magnesium deficiency while taking the heartburn and gastro-esophageal reflux disease treatment.

While Public Citizen cites extensive PPI research, some research contradicts the group’s assessment and some practitioners disagree with the group’s recommendations.

FDA Already Disagrees

FDA is among the dissenters for at least two of the warnings Public Citizen recommends for OTCs, fracture and hypomagnesemia risks.

Earlier this year, FDA excluded OTC PPIs from a warning that prolonged use of Rx PPIs could cause magnesium deficiency. The agency reasoned that OTC PPIs – such as Prilosec OTC (omeprazole), Prevacid 24HR (lansoprazole) and Zegerid OTC (omeprazole/sodium bicarbonate) – posed “very little risk of hypomagnesemia” when used as directed because of their low doses and limited 14-day treatment (Also see "In Brief" - Pink Sheet, 7 March, 2011.).

For similar reasons, FDA determined labels for OTC PPIs need not include warnings about increased risk of hip, wrist and spine fractures after initially requiring the warning “as a precaution.” The agency said research showed the greatest fracture risk came from long-term use of prescription PPIs (Also see "In Brief" - Pink Sheet, 28 March, 2011.).

Public Citizen, however, asks FDA to reinstate the fracture-risk warning on OTCs because, as the agency acknowledges in a March 2011 Drug Safety Communication, “consumers … may take these products for periods of time that exceeds the directions on the OTC label.”

The group also contends OTC PPIs need the warning because patients and doctors might substitute nonprescription products for more expensive Rx versions for long-term therapy.

FDA acknowledged but discounted this risk when it determined the warning on OTC PPIs was unnecessary.

Public Citizen’s petition also says prolonged use of OTC PPIs against label directions elevates the risk of hypomagnesemia, warranting a warning.

The petition adds that consumers taking OTC PPIs might take other magnesium-reducing medications, such as diuretics, and thus “need to be warned of this potentially life-threatening side effect.”

Public Citizen acknowledges FDA “has taken a good first step in its move to include this risk information under the Highlights section of all prescription PPIs,” but it says the agency should alert users more prominently with black box warnings because use can cause fatal cardiac arrhythmias and life-threatening complications.

With regards to increased risk of infection, the group complains that PPIs place users at an increased risk of pneumonia, but such a warning is missing from all labels (Also see "Heartburn Drug Use Connected To Higher Pneumonia Risk – JAMA Study" - Pink Sheet, 1 November, 2004.).

Further, information on clostridium difficile bacteria, which is associated with the development of severe diarrhea and is known to increase when stomach acid is suppressed, is listed on only Nexium, Prilosec and Vimovo but is attributed to all PPIs (“JAMA Study Links Gastric Acid-Suppressing Drugs To Increased Diarrhea Risk,” “The Tan Sheet” Dec. 21, 2005).

Public Citizen Argues PPIs Are “Addictive”

Public Citizen also pushes for a black box warning about the “addictive nature” of PPIs due to an increased risk of “rebound hypersecretion,” which can occur when patients discontinue the drug. The group points to studies on healthy volunteers showing that “in as little as four weeks” PPI users produce even more gastric acid to compensate for the acid-suppressing therapy.

However, conflicting research calls into question the extent or intensity of rebound hypersecretion following short-term use and could undermine Public Citizen’s call for a warning about PPIs’ potentially addictive nature on OTC products.

Researchers led by David Metz, with the Division of Gastroenterology at the University of Pennsylvania School of Medicine, recently found heartburn symptoms did not worsen beyond baseline levels within two months of discontinuing four to eight weeks of PPI therapy, according to a study published online Aug. 16 in the American Journal of Gastroenterology.

The retrospective analysis was of data on 287 patients with documented acid-related disorders who took PPIs for four to eight weeks, significantly longer than the label directions for OTC PPIs, which limit treatment to 14 days no more than every four months.

Reflecting on his research and interactions with patients, Metz said, “short-term use is not a big concern” and Public Citizen’s proposed additional warnings are not necessary.

“If you are on the drug for six to eight weeks, a little bit of rebound is not the end of the world. If you are on the drug for months and months and months, I do believe rebound is a real potential concern, and therefore, I think you should use the lowest effective maintenance dose,” he said in an interview.

Public Citizen also advocates labels should highlight the risk of drug interactions, vitamin B12 deficiency and acute interstitial nephritis, as well as standardize the length of treatment for the prescription-only indication of GERD.

The group maintains labels for all PPIs, not just omeprazole, should mention in the “Highlights” section that PPIs could reduce the efficacy of the heart-protective drug clopidogrel, cancer-drug methotrexate and immunosuppressant mycophenolate mofetil because the risk could be class wide (Also see "PPI-Clopidogrel Shows Benefit, But Omeprazole Concern Remains - Study" - Pink Sheet, 22 March, 2010.).

The group also worries acute interstitial nephritis may be a class-wide effect of PPI use, based on a systematic review published in 2007. It argues more evidence is needed, but that the existing evidence should be placed on the label.

Inappropriate PPI Use Impetus For Warning

One of the drivers for Public Citizen’s petition is the increasing use of PPIs and the hope that “the added risk information, and provider and patient awareness of appropriate PPI use, should help to limit the massive amount of needless overprescribing,” the group says.

It notes that PPIs, with 119 million prescriptions dispensed in 2009, are “one of the most widely used classes of drugs in the U.S.,” and the majority of this use is “probably inappropriate and with minimal or no benefit to the patient.”

It concludes, “FDA must act immediately to require disclosure of the risk information … to ensure that the benefits of PPIs are appropriately balanced with their harms.”

Two physicians at the Northwestern University Feinberg School of Medicine agree PPIs are sometimes misused. They write in an editorial in the American Journal of Gastroenterology that “in the absence of demonstrable benefit, whatever trivial risks exist related to chronic PPI use will dominate a risk-benefit assessment.”

However, they add, “PPI treatment remains an important, valuable and safe intervention for a multitude of patients with appropriate indications.”

Metz agreed, “PPIs are the most fantastic drug for switching off gastric acid secretion They are infinitely better than the alternatives which are H2 receptor antagonists because they are more effective, more predictable and, I think, in the big picture generally speaking, in terms of acute side effects, they are as safe or safer.”

By Elizabeth Crawford

Public Citizen Urges FDA To Add Sweeping Warnings To PPI Labels

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