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FDA: Possible Fracture Risk with High Dose, Long-term Use of Proton Pump Inhibitors
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Labeling changes will include new safety information
FDA NEWS RELEASE
For Immediate Release: May 25, 2010
Media Inquiries: Elaine Gansz Bobo, 301-796-7567, elaine.bobo@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA: Possible Fracture Risk with High Dose, Long-term Use of Proton Pump Inhibitors
Labeling changes will include new safety information
The U.S. Food and Drug Administration today warned consumers and health care professionals about a possible increased risk of fractures of the hip, wrist, and spine with high doses or long-term use of a class of medications called proton pump inhibitors. The product labeling will be changed to describe this possible increased risk.
Proton pump inhibitors, available by prescription and over-the-counter (OTC), work by reducing the amount of acid in the stomach. Prescription proton pump inhibitors include esomeprazole (Nexium), dexlansoprazole (Dexilant), omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (Aciphex). Prescription proton pump inhibitors are used to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus.
OTC versions, used for the treatment of frequent heartburn, include omeprazole (Prilosec OTC, Zegerid OTC) and lansoprazole (Prevacid 24HR).
"Epidemiology studies suggest a possible increased risk of bone fractures with the use of proton pump inhibitors for one year or longer, or at high doses," said Joyce Korvick, M.D., deputy director for safety in FDA's Division of Gastroenterology Products. "Because these products are used by a great number of people, it's important for the public to be aware of this possible increased risk and, when prescribing proton pump inhibitors, health care professionals should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition."
FDA's warning and decision to revise the labeling of proton pump inhibitors are based on the Agency's review of several epidemiological studies that reported an increased risk of fractures of the hip, wrist and spine in patients using proton pump inhibitors. Both the Warnings and Precautions section of the prescription labeling and the Drug Facts label on OTC proton pump inhibitors will address these findings.
Health care professionals and consumers should weigh the known benefits against the potential risks of proton pump inhibitors when determining if these medications are appropriate for treatment. Consumers also should talk with their health care professional about any concerns.
Any side effects or other product problems with proton pump inhibitors should be reported to FDA's MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling 800-332-1088.
For more information:
Drug Safety Communication1
Consumer Update: Possible Increased Risk of Bone Fractures With Certain Antacid Drugs
Safety Announcement
[05-25-2010] The U.S. Food and Drug Administration (FDA) is revising the prescription and over-the-counter (OTC) labels for a class of drugs called proton pump inhibitors to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.
Proton pump inhibitors work by reducing the amount of acid in the stomach. Nexium, Dexilant, Prilosec, Zegerid, Prevacid, Protonix, Aciphex, and Vimovo are available by prescription to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus. Prilosec OTC, Zegerid OTC, and Prevacid 24HR are sold over-the-counter (OTC) for the treatment of frequent heartburn.
The new safety information is based on FDA's review of several epidemiological studies that reported an increased risk of fractures of the hip, wrist, and spine with proton pump inhibitor use. Some studies found that those at greatest risk for these fractures received high doses of proton pump inhibitors or used them for one year or more (see Data Summary section).The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture primarily was observed in this age group.
While the greatest increased risk for fractures in these studies involved people who had been taking prescription proton pump inhibitors for at least one year or who had been taking high doses of the prescription medications (not available over-the-counter), as a precaution, the "Drug Facts" label on the OTC proton pump inhibitors (indicated for 14 days of continuous use) also is being revised to include information about this risk.
Healthcare professionals and users of proton pump inhibitors should be aware of the possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors, and weigh the known benefits against the potential risks when deciding to use them.
Additional Information for Patients and Consumers
Proton pump inhibitors are effective in treating a variety of gastrointestinal disorders. Do not stop taking your proton pump inhibitor unless told to do so by your healthcare professional.
Be aware that an increased risk of fractures of the hip, wrist, and spine has been reported in some studies of patients using proton pump inhibitors. The greatest increased risk for these fractures was seen in patients who receive high doses of these medications or use them longer (a year or more).
Read and follow the directions on the OTC Drug Facts label, when considering use of OTC proton pump inhibitors.
Be aware that the OTC proton pump inhibitors should only be used as directed for 14 days for the treatment of frequent heartburn. If your heartburn continues, talk to your healthcare professional. No more than three 14-day treatment courses should be used in one year.
Talk to your healthcare professional about any concerns you may have about using proton pump inhibitors.
Report any side effects with proton pump inhibitors to FDA's MedWatch program using the information at the bottom of the page in the "Contact Us" box.
Additional Information for Healthcare Professionals
Proton pump inhibitors provide important benefits for many patients in treating or preventing conditions such as erosive esophagitis, nonsteroidal anti-inflammatory drug-induced ulcers and gastroesophageal reflux disease.
Be aware of the increased risk of fractures of the hip, wrist, and spine seen in some observational studies in patients using proton pump inhibitors.
When prescribing proton pump inhibitors, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.
Follow the recommendations in the product labeling when prescribing proton pump inhibitors.
Individuals at risk for osteoporosis should have their bone status managed according to current clinical practice, and should take adequate vitamin D and calcium supplementation.
Report any adverse events with proton pump inhibitors to FDA's MedWatch program using the information at the bottom of the page in the "Contact Us" box.
Data Summary
To date, randomized clinical trials of proton pump inhibitors have not found an increased risk of fractures of the hip, wrist, or spine. These studies are generally six months in duration and there is limited information on effects of higher than recommended doses.
The decision to revise the Warnings and Precautions section of the prescription labeling as well as the OTC Drug Facts label for proton pump inhibitors is based on FDA's review of the findings from seven published epidemiological studies.1-7 These studies used claims data from computerized administrative databases to evaluate the risk of fractures of the hip, wrist, and spine in patients treated with proton pump inhibitors compared to individuals who were not using proton pump inhibitors (The findings from these studies are found in the Table below).
In these studies:
- Six reported an increased risk of fractures with the use of proton pump inhibitors1,2,3,5,6,7.
- Exposure to proton pump inhibitors ranged from a period of 1 to 12 years, depending on the study.
- The emergence of fractures varied among studies; with one study reporting an increase in fractures with use of proton pump inhibitors in the previous year 2 and another study finding an increase after 5 to 7 years of proton pump inhibitor use3.
- The increased risk of fractures was primarily observed in older individuals.
- Two studies reported an increase in fractures with higher doses of proton pump inhibitors2,5.
- Two studies reported an increase in fractures with longer duration of use 2,3.
- One study did not find a relationship between proton pump inhibitor use and fractures 4. This study limited the study population to those without major risk factors for fracture.
FDA does not have access to the data or the protocols for these studies, so our ability to verify that the studies were conducted as described in the original publications is limited. Based on our review of the published articles, the key strengths of these studies are that they appear well-designed, considered the effects of both dose and duration of use of proton pump inhibitors on fracture risk, and used appropriate statistical methods to reduce bias by adjusting for potential factors that are known to be associated with the occurrence of fractures such as age, gender, presence of co-existing conditions and use of co-prescribed medications.
Several study limitations, however, make understanding the clinical relevance of the reported findings difficult to determine. Administrative claims databases do not typically contain information on all potential factors that could influence the relationship between proton pump inhibitors use and fracture risk. These studies were not able to account for missing or incomplete information on family history of osteoporosis, smoking history, weight and height measurements, alcohol use, history of dietary and supplement use (calcium and vitamin D), OTC medication use, presence of digestive diseases, such as ulcers, reasons for proton pump inhibitor use, and recent history of immobility, dizziness, or falls. In addition, in most studies where a possible link with osteoporotic fracture was reported, no information was collected about the timing of proton pump inhibitor use in relation to onset or worsening of osteoporosis.
However, the exact mechanisms for an increased risk of fractures with proton pump inhibitor use are not known. Three epidemiologic studies found no consistent association between chronic proton pump inhibitor use and bone mineral density 6,7,8.
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.
To further investigate this issue, the FDA plans to analyze data from several large, long-term, placebo-controlled clinical trials of bisphosphonates (drugs used to prevent fractures) to assess the risk of fractures in women at risk for osteoporosis-related fractures who used or did not use proton pump inhibitors.
FDA is also working with the manufacturers of these products to further study this possible risk. For example, as part of the Dexilant (dexlansoprazole) approval, (January 2009), the manufacturer was required to perform a postmarketing clinical trial to evaluate the effects of dexlansoprazole and esomeprazole on bone homeostasis, including changes in biomarkers of bone formation and bone resorption.The results from this trial are expected at the end of 2011.
In summary, the available data, including findings from several epidemiological studies, suggest a possible increased risk of fractures of the hip, wrist, and spine in patients using proton pump inhibitors. The data suggest that the increased risk may be dependent upon dose, duration of use, or both. At the present time, there is uncertainty about the magnitude of this risk. In light of this uncertainty, when prescribing proton pump inhibitors, healthcare professionals should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.
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