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FDA panel okays revised osteoporosis indication for PremPro: discussion of WHI data.

BETHESDA, MD. -- An independent expert panel convened by the Food and Drug Administration has agreed that the revised osteoporosis indication for PremPro, changed earlier this year to reflect the findings of the Women's Health Initiative, is adequate.

The FDA's Endocrinologic and Metabolic Drugs Advisory Committee panel came to this consensus at the end of a meeting called by the agency to review data from the trial and consider the implications of long-term use of these products for the prevention and/or treatment of postmenopausal osteoporosis.

This was the first time Women's Health Initiative (WHI) data have been discussed at an FDA advisory panel meeting.

In January, the osteoporosis indication for PremPro (conjugated estrogens/medroxyprogesterone, 0.625 / 2.5 and 0.625 / 5) and Premarin (conjugated estrogens) was updated to include the statement that when these products are prescribed "solely" for the prevention of postmenopausal osteoporosis, approved nonestrogen treatment should be carefully considered, and estrogens and combined estrogen-progestin products should be considered only for women with a significant risk of osteoporosis that outweighs the risks of the drug.

The same label changes applied to the lower dose formulations of PremPro (0.45 mg/1.5 mg and 0.3 mg/1.5 mg) when they were approved in April and June, respectively.

"Collectively, we can't think of a better way" to state the information on the osteoporosis indication, said acting panel chair Michael McClung, director of the Oregon Osteoporosis Center, Portland. The changes clarify that the use is for prevention and not treatment, he said, and the reminder that there are alternative therapies for preventing bone loss represents "great progress."

At the meeting, principal investigators from the WHI trial of estrogen and progestin in postmenopausal women and officials from the FDA and Wyeth, the maker of PremPro, made presentations on the data and implications of the estrogen-progestin arm of the WHI, including a recently published analysis of the osteoporosis data. (See story on p. 1, continued above.) That study concluded that, despite the increased bone mineral density and reduction in fracture risk associated with the use of PremPro in postmenopausal women, it should not be recommended for preventing or treating osteoporosis in women who don't have vasomotor symptoms, "given the overall unfavorable risk-benefit ratio and the availability of other agents" (JAMA 290[13]: 1729-38, 2003).

In January the FDA announced that the labeling of all estrogen and estrogen-progesterone products needed to include a black box warning on the increased risk of heart disease, MI, and stroke associated with therapy, based on the WHI data, and that the osteoporosis and vulvar and vaginal atrophy indications would be revised to include consideration of other available treatments before prescribing hormone therapy (HT).

The FDA has requested that manufacturers of other estrogen-progestin products make the same revisions in their labeling.

At the meeting, Dr. Joseph Camardo of Wyeth Pharmaceuticals, Philadelphia, emphasized that the revised label did not need to be changed further at this time. He cited evidence that practitioners have been changing their prescribing practices to be consistent with the new recommendations: 4 months after the low-dose PremPro (0.45/1.5) became available in July, 25% of all new Prempro prescriptions had been written for this product, and 94% of women who currently start PremPro initiate therapy for treatment of menopausal symptoms. The majority of those women are younger than the women in WHI, whose mean age was 63 years.

Dr. Camardo took issue with the global index, the tool used to calculate the overall risk-benefit in the recent JAMA analysis, which he said is used to evaluate population results in a clinical trial and is not a risk-management tool for individual patients, who may not closely match the population in the WHI.

That study was not designed to assess the use of estrogen and progestin in women closer to menopause, who are experiencing bone loss and menopausal symptoms. Most women who take estrogen/progestin are younger than the women in WHI and may be at less risk, he said.

Individualizing the decision to use HT for postmenopausal osteoporosis prevention was also emphasized in a statement issued by the American College of Obstetricians and Gynecologists at the meeting. Although the global index concept "is potentially useful from a public policy perspective, it falls short as guidance for care of individual patients. Ultimately, this weighing of benefit and risk must be done by each individual physician with each individual patient," the statement said.

The FDA advisory panel recommended conducting future studies of transdermal products and a prospective study of estrogen-progestin therapy in early menopausal women, who were not well represented in the WHI. Efforts should be made to determine how to identify women at risk for rapid postmenopausal bone loss who clearly would be targeted for short-term, low-dose estrogen-progestin therapy, one panelist said.
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Author:Mechcatie, Elizabeth
Publication:OB GYN News
Date:Nov 1, 2003
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