Bone drugs from Warner Chilcott Plc, Roche Holding AG, Merck & Co. and Novartis AG need labeling changes to reduce the risk of fractures, a U.S. panel said.
The FDA should call for clarifications on the length of time that osteoporosis patients should take the medicines, outside advisers to the Food and Drug Administration said today in a 17-6 vote in Adelphi, Maryland. The FDA isn’t required to follow its panels’ recommendations.
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.”
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.
“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.
“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.
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.”