We’re at the U.S. Food and Drug Administration with the Division of Drug Information pharmacists. Today they are discussing new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. This is FDA Drug Info Rounds, a program by pharmacists for pharmacists.
Ever since FDA announced it was requiring revisions to the labels for proton pump inhibitors, or PPIs, to include information about the possible increased risk of fractures of the hip, wrist, and spine, we have been getting a lot of questions from concerned patients taking these medications.
I’m sure pharmacists in the community have been receiving many questions too! PPIs are available by prescription and OTC and are used by many people for a variety of indications.
That’s true. 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 PPI use.
Some studies found that those at greatest risk for these fractures received high doses of PPIs or used them for a year or more. The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture was primarily observed in this age group.
That’s interesting because patients are already asking whether or not this risk applies to OTC products which are only indicated for 14 days.
While the greatest increased risk for fractures in these studies involved people who had been taking prescription PPIs for at least a year or who had been taking high doses of the prescription PPIs, as a precaution, the "Drug Facts" label on the OTC products is also being revised to include information about this risk.
The decision to revise the Warnings and Precautions section of the prescription labeling as well as the OTC Drug Facts label for PPIs is based on FDA's review of the findings from seven published epidemiological studies. 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 PPIs compared to those not using PPIs.
In these studies:
- Six reported an increased risk of fractures,
- Exposure to PPIs 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 PPIs in the previous year and another study finding an increase after 5 to 7 years of PPI use.
- The increased risk of fractures was primarily observed in older individuals.
- Two of the studies reported an increase in fractures with higher doses of PPIs.
- While, two studies reported an increase in fractures with longer duration of use.
And one study did not find a relationship between PPI use and fractures. This study limited the study population to those without major risk factors for fracture.
Lesley, you mentioned high dose a moment ago. That’s an important aspect to clarify. “High dose” was a definition used in these studies. All FDA approved PPI labels provide dosing recommendation for once daily dosing, so anything that is used at a greater frequency is considered “high dose”.
To date, the randomized clinical trials submitted to FDA for approval of the PPIs, have not found an increased risk of fractures of the hip, wrist, or spine. These studies were generally six months in duration and there is limited information on effects of higher than recommended doses.
The new safety information is based on FDA's review of several epidemiological studies which looked back at patients over a period of 1 to 12 years.
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 PPIs 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 PPI 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 supplement use such as 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 PPI use in relation to onset or worsening of osteoporosis.
To further investigate this issue, FDA plans to analyze data from several large, long-term, placebo-controlled clinical trials of bisphosphonates, which are drugs used to prevent fractures, to assess the risk of fractures in women at risk for osteoporosis-related fractures who did or did not use PPIs.
So in summary:
- Pharmacists should be aware of the increased risk of fractures of the hip, wrist, and spine seen in some observational studies in patients using PPIs.
- When recommending PPIs, pharmacists should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.
- In addition, they should follow the product labeling when recommending PPIs.
Right, and when addressing the concerns of patients:
- Pharmacists should emphasize that PPIs are effective in treating a variety of gastrointestinal conditions and remind patients not to stop taking their PPI unless directed by their healthcare professional.
- They should also recommend that 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.
- Also, pharmacists should remind patients that the OTC PPIs should only be used as directed for 14 days for the treatment of frequent heartburn, and no more than three 14-day treatment courses should be used in one year. If their heartburn continues, they should talk to their healthcare professional.
- And finally, pharmacists should encourage patients to talk about any concerns they have about their PPIs.
Thanks for joining the FDA pharmacists at their Drug Info Rounds. This is our FDA program of pharmacists helping pharmacists educate consumers, so they can make better medication choices.
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