New Warnings on Common Heartburn Drugs: Too Little — and, for Some, Too Late

To say that the Food and Drug Administration (FDA) often delays action in response to critical drug and medical device safety issues is an understatement. Worst Pills, Best Pills News subscribers know this all too well. In case after case for more than two decades, you have been warned about serious drug safety concerns months or even years before the FDA notifies the public.[1]

The latest such example came in October 2014, when the FDA responded to Public Citizen’s 2011 petition asking for stronger label warnings on a class of medications commonly used to treat heartburn known as proton pump inhibitors (PPIs).[2] The belated response — sent more than three years after the petition was filed — came only after Public Citizen sued the agency for unreasonably delaying action on the petition.[3]

In its response letter, the FDA acknowledged that most of the risks identified in the petition were, in fact, likely side effects of PPI use, and it agreed to include some warning language on these risks on the product labels of all PPIs. However, the agency declined our request to require black-box warnings, the most prominent label warnings, for the four most serious risks.

About PPIs

PPIs suppress the production of stomach acid and are used to treat heartburn and a number of other conditions. There are six distinct prescription PPI medications available in the U.S., three of which are also available over the counter. PPIs are one of the most widely used classes of drugs in the U.S., with 130 million prescriptions written for these medications in 2013.[4] (See this table, from our November 2011 issue, for a list of PPIs available in the U.S.)

PPIs benefit many patients with serious illnesses, such as peptic ulcer disease, and those taking certain medications known to harm the stomach lining (for example, non-steroidal anti-inflammatory drugs, or NSAIDs).

However, PPIs are much more widely prescribed for milder conditions such as heartburn[5] — and often, as numerous studies have shown,[6],[7] for no approved use whatsoever. Patients with such conditions receive little or no benefit from their PPI pills, while being exposed to the drugs’ multiple risks. And the average PPI user is usually not aware of these risks due to inadequate information in the drugs’ labels.

Public Citizen’s petition

In its August 2011 petition, Public Citizen asked that the FDA require black-box warnings on all PPIs for the following, most serious risks:[8]

• Long-term dependency caused by rebound excess production of stomach acid when patients try to discontinue PPI use
• Osteoporosis-related fractures of the hip, wrist and spine
• Infections leading to diarrhea or pneumonia
• Dangerously low magnesium blood levels

The petition also asked for less prominent warning language on the following risks:

• Vitamin B12 deficiency
• Kidney injury
• Interactions between PPIs and the following drugs: the blood thinner clopidogrel (PLAVIX); the anti-transplant-rejection drug methotrexate (OTREXUP, RASUVO, TREXALL); and mycophenolate mofetil (CELLCEPT), a drug used to treat rheumatoid arthritis and other serious conditions

Finally, the petition urged the FDA to require that pharmacists distribute FDA-approved medication guides with every PPI prescription in order to inform patients about these side effects, and that manufacturers send a letter to all U.S. physicians informing them of PPIs’ risks.

Previous FDA actions and current response

The FDA agreed with Public Citizen that most of the risks identified in the petition were likely side effects of PPI use. In fact, before Public Citizen filed its petition, the FDA had already issued safety communications and had required (non-black-box) label warnings notifying the public and physicians about the interaction with clopidogrel (although the agency limited this warning to only one PPI, omeprazole [PRILOSEC])[9] and the risks of fractures[10] and low magnesium levels.[11]

The agency subsequently took some actions on the safety of PPIs before formally responding to Public Citizen’s petition. Six months after the petition was filed, the FDA issued a safety communication on a particularly severe form of diarrhea, caused by infection with the C. difficile bacteria, associated with PPI use.[12] In addition, about a year after the petition’s filing, the FDA required that patient medication guides be issued with all prescription PPI-containing products.[13] These guides mention some, but not all, of the risks Public Citizen pointed out in the 2011 petition.

In its October 2014 response, the FDA acknowledged the existence of most of the remaining risks identified in Public Citizen’s petition.[14]

The only two adverse events identified in Public Citizen’s petition that the FDA claimed were not side effects of PPIs (in spite of extensive evidence to the contrary cited in the petition) were pneumonia and the risk of long-term dependency.[15]

However, despite acknowledging most of the serious risks documented in Public Citizen’s petition, the FDA refused to require black-box warnings for any of the side effects because it deemed them not severe or frequent enough to warrant such warnings.[16] Instead, the agency indicated it would include language warning of the risks (except pneumonia and dependency) in less prominent locations within the drugs’ labels.

Most patients, and even physicians, probably will not read the fine print within the drugs’ labels, thereby missing the crucial warnings. For the large number of patients who do not need to be on PPIs in the first place, the less prominent warnings will lead to them unknowingly and unnecessarily incurring life-threatening risks for as long as they use the medications — which, for many patients, means years or even a lifetime.

What You Can Do

If you have a serious condition for which PPIs are approved, such as peptic ulcer disease, or if you take an NSAID, the drugs can be beneficial and even lifesaving. If you have heartburn, however, you should take PPIs only if your heartburn is severe and other, safer approaches have failed.

Heartburn is an extremely common condition, and for most people, symptoms are not that severe and come and go. While anyone experiencing symptoms should see a doctor first to rule out more serious conditions, very few people actually need medications for heartburn. Most people can resolve their symptoms through minor diet and lifestyle changes.

These changes include maintaining a healthy weight; eating smaller meals; not eating too close to bedtime; avoiding certain “trigger” foods and drinks, such as alcohol, coffee, chocolate, and fried or fatty foods; and raising the head of the bed at night.[17] For those who still experience symptoms after applying these and other lifestyle strategies, safer medications can be tried before resorting to PPIs. If over-the-counter antacids do not work, your doctor may prescribe a class of medications known as histamine-2 blockers, which also suppress stomach acid but not as potently as (and therefore with fewer side effects than) PPIs.[18]

If PPIs are eventually required, they should be used for the shortest duration and at the lowest dose necessary to relieve your heartburn symptoms.

References

[1] WorstPills.org. List of Do Not Use drugs withdrawn from the U.S. market. /chapters/view/68. Accessed December 3, 2014.

[2] Public Citizen press release. FDA’s partial approval of Public Citizen’s petition for stronger warnings on certain proton pump onhibitor products comes too late. November 3, 2014. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=4324. Accessed December 2, 2014.

[3] Public Citizen press release. Public Citizen sues FDA for failing to take action on petition concerning dangerous proton pump inhibitors. April 30, 2014. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=4157. Accessed December 2, 2014.

[4] Public Citizen press release. FDA’s partial approval of Public Citizen’s petition for stronger warnings on certain proton pump inhibitor products comes too late. November 3, 2014. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=4324. Accessed December 2, 2014.

[5] Reimer C, Bytzer P. Clinical trial: long-term use of proton pump inhibitors in primary care patients - a cross sectional analysis of 901 patients. Aliment Pharmacol Ther. 2009 Oct;30(7):725-32.

[6] Ahrens D, Chenot JF, Behrens G, Grimmsmann T, Kochen MM. Appropriateness of treatment recommendations for PPI in hospital discharge letters. Eur J Clin Pharmacol. 2010;66(12):1265-1271.

[7] Heidelbaugh JJ, Goldberg KL, Inadomi JM. Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Am J Manag Care. 2010 Sep;16(9):e228-234.

[8] Public Citizen. Petition urging FDA to add warnings to proton pump inhibitors. August 23, 2011. http://www.citizen.org/documents/1964.pdf. Accessed December 2, 2014.

[9] Food and Drug Administration. Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). November 17, 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Accessed December 2, 2014.

[10] Food and Drug Administration. Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. May 25, 2010 (updated March 23, 2011). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm. Accessed December 2, 2014.

[11] Food and Drug Administration. Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs). March 2, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm245011.htm. Accessed December 2, 2014.

[12] Food and Drug Administration. Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). February 8, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm. Accessed December 2, 2014.

[13] Food and Drug Administration. Medication guides. http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm. Accessed December 2, 2014.

[14] Food and Drug Administration. Final response to Public Citizen PPI petition. October 31, 2014. http://www.citizen.org/documents/1964_FDA%20Partial%20Petition%20Approval%20and%20Denial%20of%20PPI%20Petition_October%2031,%202014.pdf. Accessed December 2, 2014.

[15] Food and Drug Administration. Final response to Public Citizen PPI petition. October 31, 2014. http://www.citizen.org/documents/1964_FDA%20Partial%20Petition%20Approval%20and%20Denial%20of%20PPI%20Petition_October%2031,%202014.pdf. Accessed December 2, 2014.

[16] Public Citizen Press Release. FDA’s partial approval of Public Citizen’s petition for stronger warnings on certain proton pump inhibitor products comes too late. November 3, 2014. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=4324. Accessed December 2, 2014.

[17] Mayo Clinic. GERD: Lifestyle and home remedies. http://www.mayoclinic.org/diseases-conditions/gerd/basics/lifestyle-home-remedies/con-20025201. Accessed December 2, 2014.

[18] Public Citizen. Petition urging FDA to add warnings to proton pump inhibitors. August 23, 2011. http://www.citizen.org/documents/1964.pdf. Accessed December 2, 2014.