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FDA Panel: Osteoporosis Drugs Need Better Labels
  Time Limits on the Drugs Are Suggested, but How Much Time Is Yet to Be Determined
Briefing Information for the September 9, 2011 Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee
By Rita Rubin WebMD
Sept. 9, 2011 -- Labels on bisphosphonates, a type of medication used to treat and prevent osteoporosis, should further clarify how long patients can take them, an FDA advisory panel voted today.
But the panel backed off giving any specific time limits.
Bisphosphonates include Aclasta, Actonel, Altevia, Boniva, Fosamax, and Reclast. Four million to 5 million Americans fill prescriptions for the drugs every year, according to the FDA
The FDA convened the meeting because of emerging safety concerns related to long-term use -- generally considered more than three to five years -- of bisphosphonates.
In particular, the agency has received reports of osteonecrosis, or bone death, of the jaw and unusual fractures of the femur, or thigh bone, in women who had taken the drugs for several years or more.
Meanwhile, some research suggests that because bisphosphonates remain in bone for years, women could still benefit after they stop taking them.
A Visual Guide to Osteoporosis
More Information Needed on Labels
The panel, made up of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee, voted 17 to 6 in favor of recommending additional labeling information about the drugs' long-term safety and effectiveness.
The FDA usually but not always follows its advisory committee's recommendations. The agency's own analysis concluded that in women who continue bisphosphonate therapy after five years of use there's no clear benefit or evidence of harm and no subset of patients who have a "clear and consistent" reduced fracture risk, FDA scientist Theresa Kehoe, MD, told the panel.
Bisphosphonate labels mention that safety and effectiveness information is based on one to four years -- depending on the drug -- of clinical trial data, Kehoe said, but optimal length of use is unknown.
"This is really an issue that's front and center in primary care," said Douglas Bauer, MD, a University of California, San Francisco, primary care doctor invited by the FDA to address the advisory panel.
While not an ideal study to examine long-term use, the only published study to do so involved Fosamax, Bauer said. That study randomly assigned women who'd taken Fosamax daily for five years in a clinical trial to either continue taking the drug for another five years or stop.
For fractures other than those of the spine, there was no evidence overall of continued benefit after five years, Bauer said.
But there was a 55% reduction in spine fracture risk in women who continued taking Fosamax for the extra five years, said Arthur Santora, executive director of clinical research for diabetes and endocrinology drugs at Merck, which makes the drug.
And in studies of up to 10 years of use, Santora said, there were no reports of jawbone death and no difference in the risk of unusual thigh fractures between women who took the drug and those who didn't.
Long-Term Use of Bisphosphonates
Panelists noted that it's difficult to predict which women will benefit from long-term bisphosphonate use. The Fosamax study did find that women's bone mineral density at the time they discontinued the drug was strongly related to their fracture risk over the next five years, Bauer told panel members.
The findings probably can be generalized to weekly dosing of Fosamax, he said, but it's unclear how they relate to other bisphosphonates.
Paul Miller, MD, medical director of the Colorado Center for Bone Research, noted that long-term use wasn't an issue when bisphosphonates first came on the market. At that time, "we didn't treat a lot of women in their 50s or early 60s with bisphosphonates," said Miller, who was representing Warner Chilcott, maker of Actonel. "We treated sicker women in their 70s and 80s."
In July 2002, the first published results from the Women's Health Initiative changed all that, he said. The study found that Premarin, the top-selling brand of postmenopausal estrogen, increased heart attack, stroke, and breast cancer risk. Postmenopausal women who had been on hormone therapy to protect their bones flooded doctors' offices in search of an alternative, Miller said.
Most of the bisphosphonate patients who testified before the panel about their unusual thigh fractures said they had started taking the drugs in their 50s or 60s. Some of the women said they'd been prescribed the drugs for osteopenia, which means their bone mineral density was lower than normal but not low enough to be classified as osteoporosis.
Advisory committee member Clifford Rosen, MD, director of the Center for Clinical and translational Research at the Maine Medical Center Research Institute in Scarborough, questioned the wisdom of prescribing bisphosphonates simply to prevent osteoporosis, as opposed to treating it.
"A prevention indication, I think, is being revisited all the way around, including by the FDA," Kehoe said in response. "Certainly it's something we're struggling with and dealing with."
The agency has evaluated the safety of the drugs, known as bisphosphonates, for almost four years and cited possible links to unusual thigh fractures and jawbone deterioration in 2010. The drugs are taken most often by post-menopausal women who have osteoporosis. The agency said in July it also was examining conflicting studies on whether bisphosphonate pills such as Warner Chilcott's Actonel, Merck's Fosamax and Roche's Boniva raise esophageal cancer risks. A revised label should "be very clear that efficacy may fall off after a period of time, perhaps five years," panelist Lewis Nelson, director of the medical toxicology fellowship program at New York University, said after the vote. "Serious concerns have been raised about risk, and those need to be continually evaluated as well."
Drug Sales
Bisphosphonates generated $4.2 billion in U.S. sales last year and $7.6 billion worldwide, according to IMS Health Inc. in Norwalk, Connecticut.
Warner Chilcott, based in Dublin, had $1.03 billion in Actonel sales in 2010, according to Bloomberg data. Boniva generated $975 million, while Fosamax had $926 million and Novartis's Reclast had global sales of $579 million.
Merck's Fosamax won approval in 1995 as the first bisphosphonate to treat and prevent osteoporosis in older women. Revenue from Fosamax reached $3.19 billion in 2005, then dropped as Merck, of Whitehouse Station, New Jersey, faced competition from generic copies.
About 8 million women and 2 million men in the U.S. have osteoporosis, and 34 million Americans have low bone mass that puts them at risk for the disease, Theresa Kehoe, a medical officer and team leader in the FDA's Division of Reproductive and Urologic Products, said in a presentation to the panel.
The question of how long osteoporosis patients should take bisphosphonates, and whether temporary breaks from the treatment would prove beneficial, "is really front and center to primary care," said Douglas Bauer, a professor of medicine at the University of California, San Francisco.
Patient Questions
"Many of our patients are calling, asking what to do about long-term use of bisphosphonates," Bauer, a guest speaker invited by the FDA, told the panel. Some people who take the medications have experienced "atypical fractures of the thigh" that account for less than 1 percent of all hip and femur breaks, the FDA said in an October safety announcement. The agency required Warner Chilcott, Roche, Novartis, Merck and makers of generic Fosamax to update the drugs' labels to warn of the possible link.
Unusual fractures "appear to have a strong association with bisphosphonates, although causality has not been determined," FDA staff said Sept. 7 in a preliminary review of the drugs. "There is no agreement on the extent to which cumulative use of bisphosphonates increases the risk of atypical fractures." The agency also is reviewing conflicting studies, based on data from the U.K., on whether oral bisphosphonates can increase the risk of esophageal cancer.
Inconclusive Evidence
"The available evidence regarding the possible association between oral bisphosphonates and esophageal cancer is inconclusive," FDA reviewers said in the report. "No conclusion can be reached as to whether long-term use of bisphosphonates is associated with esophageal cancer."
Data from a 10-year Merck clinical trial show that Fosamax's benefits outweigh its potential hazards in osteoporosis patients who are at risk for regular bone fractures, said Arthur Santora, executive director of clinical research at Merck Research Laboratories.
Temporary cessation of Fosamax treatment, known as a drug holiday, "may be considered for patients who are no longer considered to have a sufficiently high fracture risk," Santora told the panel. "However, neither restricting the duration of use nor implementing a drug holiday is likely to be beneficial for patients at sufficiently high fracture risk who require long-term treatment." Patient advocates urged the FDA to require label changes limiting the drugs' use to five years in osteoporosis patients.
'Serious Risks'
Treatment with bisphosphonates for more than five years "needlessly exposes patients to serious risks with no evidence of any clinical benefit," Sammy Almashat, a staff researcher at Public Citizen's Health Research Group, told the panel during a public comment period.
Committee members said the FDA should call for more research into the drugs' long-term safety and effectiveness.
"We don't have evidence of benefit" after five years, "but that doesn't mean there is evidence of a lack of benefit," panelist Maria Suarez-Almazor, a professor of internal medicine at the University of Texas MD Anderson Cancer Center in Houston, said before the vote. "I don't think we have enough data to restrict anything at this point."
Stronger Cautions Backed on Bone Drugs for Women
NY Times By DUFF WILSON, Published: September 9, 2011
Two advisory panels to the Food and Drug Administration on Friday recommended increasing the cautionary language on the product labels of bone-building drugs taken by more than five million women in the United States.
Brian Branch-Price/Associated Press
The F.D.A. is expected to issue a revised label for drugs that include Fosamax, Actonel and Boniva.
But they stopped short of specifying what the safety warnings should say and did not recommend limiting use of the drugs to a proposed five years. About 11 percent of women 55 and older take the drugs to prevent bone fractures. The medical advisers did not press the issue as strongly as the F.D.A. staff itself did in a 45-page report issued on Wednesday. The staff report said studies "suggest no significant advantage of continuing drug therapy beyond five years."
The F.D.A. is expected to issue a revised label in November for the drugs, known as bisphosphonates, including Fosamax, Actonel and Boniva.
The agency usually follows the advice of its advisory panels, but not always. The two panels met jointly on Friday to comment on the staff's broad safety review of the drugs, prompted by concerns over a relatively small number of long-term users who had suffered unusual thigh fractures or a serious jaw disease. The benefits of the drugs have only been proven for three to five years, not longer, F.D.A. staff members said, warning about links to those rare conditions after longer use.
The advisory meeting ended in a 17-6 vote on a single question put to the panel for a vote: whether the labels should "further clarify the duration of use" of the drugs. Several advisers said the question was vague. So are the current labels, which say, "The optimal duration of use has not been determined."
The F.D.A. said an estimated 9 percent of users take the drugs longer than three years, and under 1 percent take them longer than five years.
But none of the panel members recommended firm restrictions on longer-term use. None suggested a so-called black box warning, as some former patients who suffered the injuries are seeking.
Dr. Lewis S. Nelson, a toxicologist with the New York University School of Medicine, said the evidence warranted "something a little bit more dramatic," like moving the statement to the "warnings" section of the label from the section on "indications and usage."
Others said few patients heeded the label, anyway. They suggested stronger language asking doctors to review the usage annually.
Dr. Nelson is chairman of the F.D.A. Drug Safety and Risk Management Committee; it joined the Advisory Committee for Reproductive Health Drugs in the daylong review.
Dr. Clifford J. Rosen, a professor at the Tufts University School of Medicine, who voted for the new label, opposed a tougher warning for people to stop taking the drugs.
"I wouldn't put a limit of five years for therapy because that would handcuff a lot of doctors," he said.
Several advisers said the new label needed to be much more specific about benefits during the first three to five years and about the uncertainties after that. They said doctors and patients should consider a variety of factors while individually considering longer-term use of the drug.
The six people who voted against a label change said there was insufficient evidence of risk in longer use, especially with a drug proven to benefit women for the first three to five years.
"I don't want to cry wolf on this," said Dr. John M. Kittelson, a professor in the Department of Biostatistics and Informatics at the University of Colorado Denver.
Several women who have suffered the unusual fractures testified at the meeting. Dr. Jennifer P. Schneider, whose thigh broke as she was standing in a New York subway, presented her own review of 111 cases.
Almost all took the drug for more than five years, most for a pre-osteoporosis condition called osteopenia, she said. Many felt pain in the thigh before the bone suddenly broke.
The first such drug, Fosamax, was marketed by Merck in 1995. Others include Actonel and Atelvia from Warner Chilcott and Boniva from Roche Therapeutics. Worldwide sales last year were $7.6 billion.
The committee also called for more study of the overall effectiveness of the drugs in their desired goal of preventing fractures. And the advisers recommended that the F.D.A. take a close look at why the drugs are prescribed as preventive medicine for women who do not even have osteoporosis.
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