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update of Safety Review Follow-up to the October 1, 2007


Bisphosphonates: Alendronate (Fosamax, Fosamax Plus D), Etidronate (Didronel), Ibandronate (Boniva), Pamidronate (Aredia), Risedronate (Actonel, Actonel W/Calcium), Tiludronate (Skelid), and Zoledronic acid (Reclast, Zometa)

This information reflects FDA’s current analysis of available data concerning these drugs.

On October 1, 2007, FDA announced that it was reviewing safety data that raised concerns about a potential increased risk for atrial fibrillation in patients treated with a bisphosphonate drug (). An article and an accompanying letter to the editor in the May 3, 2007, issue of The New England Journal of Medicine described increased rates of serious atrial fibrillation in two different studies of women ages 65 to 89 years old with osteoporosis treated with the bisphosphonates, Reclast and Fosamax. Data available to FDA at that time, including data from the NDA approval of Reclast for osteoporosis, showed an increased risk of serious atrial fibrillation and this risk was reflected in the Reclast labeling. After our review, based on the data available at this time, healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication.

On October 1, 2007, FDA began requesting placebo-controlled clinical trial information from the sponsors of alendronate, ibandronate, risedronate, and zoledronic acid in order to explore the potential risk for atrial fibrillation in male and female patients treated with these bisphosphonate drugs.

The data submitted by the four sponsors included data on 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years.

The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. The absolute difference in event rates between each of the bisphosphonate and placebo arms varied from 0-3 per 1,000.

One large study of zoledronic acid showed a statistically significant increase in the rate of serious atrial fibrillation events. However, across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Increasing dose or duration of bisphosphonate therapy was also not associated with an increased rate of atrial fibrillation.

The FDA is aware of discordant results from the literature and from other epidemiological studies about the incidence and clinical course of atrial fibrillation in patients taking bisphosphonates. FDA is exploring the feasibility of conducting additional epidemiologic studies to examine this issue. In addition, FDA is continuing to monitor post-market reports of atrial fibrillation in patients who have taken bisphosphonates.

Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis. Bisphosphonates are also used to slow bone turnover in patients with Paget’s disease of the bone and to treat bone metastases and lower elevated levels of blood calcium in patients with cancer. There are 7 FDA-approved bisphosphonates: alendronate (Fosamax, Fosamax Plus D), etidronate (Didronel), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel, Actonel W/Calcium), tiludronate (Skelid), and zoledronic acid (Reclast, Zometa).

This follow-up communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs.