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FDA updates bisphosphonate labels to reflect increased thigh fracture risk

This article was originally published in Scrip

Executive Summary

The US FDA has requested a labeling change for all bisphosphonates used for osteoporosis, whereas the "Warnings and Precautions" section would be updated to state that there is a possible increased risk of rare but serious atypical fractures of the thigh bone (femur), known as subtrochanteric and diaphyseal femur fractures.

The agency is also requiring that a Medication Guide be given to patients when they pick up their prescription to better inform patients of the possible risks, according to the "Drug Safety Communication" posted on its website. This move formally requires the first Risk Evaluation and Mitigation Strategy (REMS) for these products.

While it is not clear whether bisphosphonates are the cause, atypical femur fractures have been predominantly reported in patients taking bisphosphonates, the FDA said in announcing the labelling change.

The labelling changes and Medication Guide will affect only those bisphosphonates approved for osteoporosis, including oral bisphosphonates such as Merck & Co's Fosamax (alendronate and generics), Warner Chilcott's Actonel (risedronate), Roche's Boniva (ibandronic acid), as well as the intravenous product Novartis's Reclast (zolendronic acid). (There have been reports of the atypical fractures in both the oral and injectable products for osteoporosis, FDA said.)

Labelling changes and the Medication Guide will not apply to bisphosphonates used for Paget's disease or cancer/hypercalcaemia such as Didronel (etidronate), Zometa (zolendronic acid) and their generic products.

"Although the optimal duration of bisphosphonate use for osteoporosis is unknown, these atypical fractures may be related to long-term bisphosphonate use", the agency stated.

In looking at the data, the agency said that the atypical fractures have predominantly occurred in patients who have taken bisphosphonates for five years or more.

The agency said doctors should periodically evaluate the need for continued bisphosphonate therapy for patients who have been on the drugs for longer than five years.

As far as data sheet changes are concerned, the FDA said that for the "Indications and Usage" sections, the labels for the products will carry a new Limitations of Use statement "describing the uncertainty of the optimal duration of use of bisphosphonates for the treatment and/or prevention of osteoporosis."

Safety concerns first arose in 2008, and the FDA had stated in March that it hadn't found a link between the drugs and typical subtrochanteric femur fractures but was continuing its safety review (scripintelligence.com, 11 March 2010). Now the agency has said it has reviewed data from clinical trials, case reports in the literature and data summarised in the American Society for Bone and Mineral Research Task Force Report. Last month that task force recommended that the FDA revise the US labels since it found that as many as 94% of the 310 cases of atypical femur fractures reviewed were also taking one of the bisphosphonates, most for more than five years (scripintelligence.com, 15 September 2010).

Ayptical subtrochanteric femur fractures are fractures in the bone joint just below the hip joint. Diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon and appear to account for less than 1% of all hip and femur fractures overall, the FDA said.

"Subtrochanteric femur fractures, or thigh bone fractures, are known to occur in patients with osteoporosis," Dr Sandra Kweder, deputy director, Office of New Drugs in the FDA's Center for Drug Evaluation and Research, told reporters on a conference call. "However, in recent years, there have been an increasing number of reports of femur fractures with some unusual features in patients taking bisphosphonates. One thing that is unusual is that they are often associated with very little or no trauma at all."

Dr Kweder described how the September 2010 report by the American Society for Bone and Mineral Research – which had relied on data from Kaiser Health - "helped [the agency] understand these fractures a little bit better and make us confident that this is something that is potentially more closely related to these drugs, particularly in long-term use, than we previously had evidence for."

A significant point about the atypical fracture is that the patients who experience them can have a fracture occurring anywhere in the femur shaft, or long bone of the thigh, Dr Kweder said. "In addition to being less likely to be associated with trauma, patients taking bisphosphonates who have experienced an atypical fracture are generally younger than those with osteoporotic fractures," she noted. "In some cases, the patients have bilateral fractures of both femurs. Importantly, many of these patients described a dull, aching thigh or groin pain that begins weeks to months before a complete fracture occurs."

In more than half of the case report forms reviewed by the FDA, patients experienced pain or aching of the groin before the fracture.

There are no guidelines for how long patients should take bisphosphonates for osteoporosis. Dr Theresa Kehoe, team leader in the division of reproductive and urological products in CDER's Office of Drug Evaluation III, told reporters that the FDA is actively evaluating the issue and is not necessarily ready to make recommendations as far as the duration of treatment, or whether drug holidays are warranted. "We are looking at all of those issues".

More than five million US patients filled prescriptions for bisphosphonates in 2009, the FDA said.

Merck claims that in clinical studies involving more than 28,000 patients, Fosamax has not been associated with increased fracture risk at any skeletal site. But last year it voluntarily added information to its US data sheet for Fosamax under post-marketing experience that low-energy femoral shaft and subtrochanteric fractures have been reported with the product.

Recently, two studies into whether bisphosphonates are associated with oesophageal cancer yielded contradictory findings (scripintelligence.com, 7 September 2010).

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