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FDA panel backs lasofoxifene for osteoporosis indication.

Rockville, MD. -- The majority of a federal advisory panel agreed that the benefits of treatment with lasofoxifene, a selective estrogen receptor modulator, would probably outweigh the risks in some postmenopausal women with osteoporosis.

At a meeting of the Food and Drug Administration's Advisory Committee for Reproductive Health Drugs, the panel voted 9-3 (with 1 abstention) that there was a population of postmenopausal women with osteoporosis for whom the benefit of treatment would likely outweigh the risks. Most panelists supported limiting the drug's use to women who are at high risk for fractures but cannot tolerate bisphosphonates.

Dr. Diane Merritt, professor of obstetrics and gynecology at Washington University, St. Louis, said she believed there was a use for lasofoxifene, but that it would be very important for physicians who prescribe the drug to appropriately counsel the patient about the associated risks.

Voting no on the risk-benefit question, Dr. Lawrence Nelson, head of the Unit on Integrative Reproductive Medicine at the National Institute of Child Health and Human Development, said that because there was still an open question about greater all-cause mortality among women on the lower dose of lasofoxifene, he found it difficult to identify a group of women to whom he would prescribe this drug. In studies, all-cause mortality was greater among women on the lower dose of lasofoxifene studied, compared with those on the higher dose and those on placebo.

Pfizer Inc. has proposed that lasofoxifene, at a dosage of 0.5 mg per day, be approved for treating osteoporosis in postmenopausal women who are at increased risk of fracture.

In a prospective, double-blind, randomized study of 8,556 postmenopausal women at increased risk of fracture, two doses (0.25 mg per day or 0.5 mg per day) of lasofoxifene were compared with placebo.

The risk of developing a new or worsening radiographic vertebral fracture within 3 years--the study's primary end point--was significantly reduced among the women who were treated with both doses of lasofoxifene, compared with those on placebo. The cumulative relative risk of developing a new or worsening radiographic vertebral fracture through the third year of treatment was reduced by 27% among those on the 0.25-mg dose, and by 41% among those on the 0.5-mg dose, compared with placebo.

Within 3 years of starting treatment, nearly 5% of those on the 0.25-mg dose and nearly 4% of those on the 0.5-mg dose developed a new or worsening radiographic vertebral fracture, compared with 6.4% of those on placebo.

The FDA had no questions regarding the drug's efficacy, and asked the panel to consider several safety issues associated with the drug that were raised in the study: a numerical increase in all-cause mortality among those treated with 0.25 mg; an increase in venous thromboembolic events (VTEs), particularly pulmonary emboli (PEs); and a significant increase in gynecologic adverse events, including increased endometrial thickness, increased vaginal bleeding, and increased uterine-related procedures.

The majority of the panel (seven panelists) said that they could not determine whether the data regarding all-cause mortality reflected a real increase in mortality among those treated with lasofoxifene; four said they did not believe this was a real increase.

The study was extended to 5 years, at which time the all-cause mortality rate was 3.2% (90 women) among those on the 0.25-mg dose, compared with 2.6% (73 women) among those on the 0.5-mg dose (the proposed dose) and 2.3% (65 women) among those on placebo. The causes of death that were more common among those on lasofoxifene were cancer (cancers of the brain, lung, and GI tract) and stroke (at 5 years, the rate of fatal stroke was 0.4% among those on the 0.25-mg dose and 0.2% among those on the higher dose and those on placebo).

The all-cause mortality rate was also higher among the women on 0.25 mg in the overall phase II/III program for the drug.

The majority of the panel (nine panelists) also agreed that the findings regarding VTEs did not elicit more concern than did the same types of events that had been associated with raloxifene (Evista) and estrogen therapies, but several panelists called for more studies of the women who develop VTEs while on these treatments.

Pfizer has developed a risk management plan to address these safety issues.

In the study, there was a significant reduction in breast cancers among the women taking 0.5 mg per day who were followed out to 5 years, but Pfizer Is not seeking approval for this claim. The FDA pointed out that breast cancer was not a primary objective of the study, and did not agree with the company's conclusion that the breast cancer risk was shown to be reduced with the drug.

The FDA usually follows the recommendations of its advisory panels. If approved, Pfizer will market lasofoxifene as Fablyn. Raloxifene, another FDA-approved SERM, is approved for osteoporosis indications.

BY ELIZABETH MECHCATIE

Senior Writer
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Title Annotation:NEWS FROM THE FDA
Author:Mechcatie, Elizabeth
Publication:Internal Medicine News
Geographic Code:1USA
Date:Nov 1, 2008
Words:827
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