FDA advisory panel suggests warning for bisphosphonates but does not specify wording

By Dr. Ananya Mandal, MDSep 12 2011

Two independent advisory panels to the Food and Drug Administration (FDA) 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. They did not however mention the exact words of the safety warnings 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. 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 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 FDA 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.” 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.

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.

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.

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.

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.”