Raloxifene

Raloxifene: The FDA approved Raloxifene to reduce the risk of invasive breast cancer in postmenopausal women in 2007. It was initially developed to treat osteoporosis.

Raloxifene (marketed as Evista by Eli Lilly and Company) is an oral selective estrogen receptor modulator (SERM) that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women.

In 2006, the National Cancer Institute announced that raloxifene was as effective astamoxifen in reducing the incidence of breast cancer in postmenopausal women at increased risk. A major adverse effect of tamoxifen is uterine cancer; raloxifene had fewer uterine cancers. Tamoxifen increased the risk of cataracts, but raloxifene did not. Both groups had more blood clots in veins and the lungs, but that side effect was more common with tamoxifen than raloxifene.^[2][3][4] On September 14, 2007, the U.S. Food and Drug Administration announced approval of raloxifene for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.^[5]

An editorial in Lancet Oncology criticized the way that information about the drug was released.^[6]

Raloxifene hydrochloride (HCl) has the empirical formula C₂₈H₂₇NO₄S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene HCl is an off-white to pale-yellow solid that is slightly soluble in water.

SERMs mimic estrogen in some tissues and have anti-estrogen activity in others. Other SERMs, such as Pfizer’s lasofoxifene and Wyeth’s bazedoxifene are in the later development phases.

Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausalwomen, for reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. For either osteoporosis treatment or prevention, supplemental calciumand/or vitamin D should be added to the diet if daily intake is inadequate.

Raloxifene is contraindicated in lactating women or women who are or may becomepregnant, in women with active or past history of venous thromboembolic events, includingdeep vein thrombosis, pulmonary embolism, and retinal vein thrombosis and in women known to be hypersensitive to raloxifene.

Common adverse events considered to be drug-related were hot flashes and leg cramps.

Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes. Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, vision changes. Raloxifene is a teratogenic drug, i.e., can cause developmental abnormalities such as birth defects.

In a 2006 study published in New England Journal of Medicine, raloxifene produced significantly more strokes and blood clots than the placebo.^[7]

A report in September 2009 from Health and Human Services’ Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene, used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.^[8]

As cancer drug

Bottle of Raloxifene

Raloxifene reduces the risk of hormone-positive breast cancer and vertebral fractures “without a shadow of a doubt,” but its effects on cardiovascular disease remain less certain, according to the results of the “Raloxifene for Use of the Heart” (RUTH) study published in the July 13, 2006 issue of the New England Journal of Medicine by Dr. Elizabeth Barrett-Connor (University of California at San Diego) and colleagues.^[9]

In the trial, in women with coronary heart disease (CHD) or multiple risk factors for CHD, raloxifene had no significant effect on the primary end point, coronary events, but it did significantly increase the risk of venous thromboembolism (VTE). And although the drug had no effect on stroke, there was a seemingly paradoxical significant increase in death from stroke.^[10]

On September 14, 2007, Steven K. Galson, the director of the United States Food and Drug Administration’s Center for Drug Evaluation and Research announced authorization of the sale of raloxifene to prevent invasive breast cancer in post-menopausal women.^[11]

Chemical synthesis

Jones, Charles D.; Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.; Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. (1984). “Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity”. Journal of Medicinal Chemistry 27 (8): 1057–66.doi:10.1021/jm00374a021. PMID 6431104.

• STAR: a head-to-head comparison of tamoxifen and raloxifene as breast-cancer preventatives
• Full Prescribing Information
• Position paper of the National Women’s Health Network
• Heringa M (2003). “Review on raloxifene: profile of a selective estrogen receptor modulator”. Int J Clin Pharmacol Ther 41 (8): 331–45. PMID 12940590.
• Barrett-Connor E (2001). “Raloxifene: risks and benefits”. Ann N Y Acad Sci 949: 295–303. doi:10.1111/j.1749-6632.2001.tb04036.x. PMID 11795366.
• Raloxifene bound to proteins in the PDB