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Home » Drug Information » FDA Approved Drugs » 2007
Medical Areas: Musculoskeletal | Obstetrics/Gynecology (Women’s Health) | Oncology | Family Medicine

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Evista (raloxifene hydrochloride)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company: Eli Lilly
Approval Status: Approved September 2007
Treatment Area: the treatment/prevention of osteoporosis and reduction of breast cancer risk in postmenopausal women

General Information

Evista (raloxifene hydrochloride) is an estrogen agonist/antagonist, referred to as a selective estrogen receptor modulator (SERM) and belongs to the benzothiophene class of compounds. The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and and the blockade of estrogenic pathways in other tissues (antagonism).

Evista is specifically approved for the treatment and prevention of osteoporosis in postmenopausal women, the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer. Evista is supplied as a 60 mg tablet designed for oral administration. The recommended initial dose of the drug is one 60 mg tablet daily, which may be administered any time of day without regard to meals.

Clinical Results

FDA Approval
FDA approval of Evista was based on the results of several clinical trials.

Treatment of Postmenopausal Osteoporosis
Effect on Fracture Incidence
This randomized, placebo-controlled, double-blind, multinational trial enrolled 7,705 postmenopausal women with osteoporosis. In the subjects with no baseline fractures, the percentage with one or more than one new vertebral fracture after three years was 1.9% in the Evista arm versus 4.3% in the placebo arm. In the subjects with one or more than one baseline fracture, the percentage of those with one or more than one additional fracture after three years was 14.1% in the Evista arm versus 20.2% in the placebo arm. In all randomized subjects the percentage with one or more than one new clinical (painful) vertebral fracture after three years was 1.8% in the Evista arm versus 3.1% in the placebo arm.

Effect on Bone Mineral Density
All women in this study received Evista (60 mg/day) in addition to calcium (500 mg/day) and vitamin D (400 to 600 IU/day). Treatment with Evista increased spine and hip BMD by 2 to 3%. It also decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for Evista (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for Evista (relative risk reduction = 30%). The increases in BMD for Lumbar Spine were as follows: 2.0 (12 months) 2.6 (24 months) and 2.6 (36 months); and for Femoral Neck were 1.3 (12 months), 1.9 (24 months) and 2.1 (36 months).

Bone Histology
Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment. Of 56 evaluable biopsies, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover. Normal bone quality was maintained, including no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone.

Effect on Endometrium
Endometrial thickness was evaluated annually in a subset of the study population (1781 subjects) for 3 years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the Evista-treated women had a 0.06 mm mean increase.

Prevention of Postmenopausal Osteoporosis
Three randomized, placebo controlled, double-blind osteoporosis prevention trials were conducted: a North American trial that enrolled 544 women; a European trial that enrolled 601 women; and an international trial that enrolled 619 women who had undergone hysterectomy. All the subjects received placebo or Evista (60 mg/day) both in combination with calcium supplementation (400 to 600 mg/day).

Effect on Bone Mineral Density
When compared to placebo the increases in BMD for each of the three studies were statistically significant at 12 months and were maintained at 24 months (p=0.001). This included BMD increases in total hip, femoral neck, trochanter, intertrochanter and lumbar spine. Evista also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward’s Triangle (hip) by 3.1% to 4.0%.

Effect on Endometrium
Endometrial thickness was evaluated from 831 women in all dose groups every 6 months for 24 months. Placebo-treated women had a 0.04 mm mean increase from baseline in endometrial thickness over 2 years, whereas the Evista treated women had a 0.09 mm mean increase.

Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis
MORE Trial
This randomized, placebo-controlled, double-blind, multinational trial evaluated the effect of Evista (60 mg/day) on the incidence of breast cancer as a secondary safety endpoint. After four years, Evista reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22-0.67). Evista also reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the Evista group compared with placebo.

CORE Trial
The effect of Evista on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE trial. The women were not re-randomized and thus continued on the 60 mg/day Evista therapy. Evista reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3.0 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the Evista group compared with placebo. There was no reduction in the incidence of ER-negative breast cancer. In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, Evista (60 mg/day) reduced the incidence of invasive breast cancer by 60% in women assigned Evista compared with placebo (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the Evista group compared with placebo.

RUTH Trial
This randomized, placebo controlled, double-blind, multinational study enrolled 10,101 postmenopausal women at increased risk of coronary events. The women were followed for a median of 5.6 years after treatment. Evista (60 mg/day) reduced the incidence of invasive breast cancer by 44% compared with placebo [absolute risk reduction (ARR) 1.2 per 1000 women-years]; this was primarily due to a 55% reduction in ER-positive invasive breast cancer in the Evista group compared with placebo (ARR 1.2 per 1000 women-years). There was no reduction in ER-negative invasive breast cancer.

Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer
STAR Trial
This randomized, double-blind trial enrolled 19,747 postmenopausal women in North America. The trial was designed to compare the effects of Evista (60 mg/day) versus tamoxifen (20 mg/day) over 5 years on reducing the incidence of invasive breast cancer. Evista was not superior to tamoxifen in reducing the incidence of invasive breast cancer. The observed incidence rates of invasive breast cancer were Evista 4.4 and tamoxifen 4.3 per 1000 women per year.

Effects on Cardiovascular Disease
In the randomized, placebo-controlled, double-blind, multinational trial, dubbed RUTH, 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, received Evista 60 mg/day. They were observed for a median follow-up of 5.6 years. No cardiovascular benefit was demonstrated after treatment with Evista and no significant increase or decrease was observed for coronary events. An increased risk of death due to stroke after treatment with Evista was observed: 59 (1.2%) Evista-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (2.2 versus 1.5 per 1000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499).

Side Effects

Adverse events associated with the use of Evista may include, but are not limited to, the following:

  • Hot Flashes
  • Body Infection
  • Arthralgia
  • Flu Syndrome
  • Rhinitis
  • Bronchitis
  • Headache

Mechanism of Action

Evista (raloxifene hydrochloride) is an estrogen agonist/antagonist, referred to as a selective estrogen receptor modulator (SERM) and belongs to the benzothiophene class of compounds. The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and and the blockade of estrogenic pathways in other tissues (antagonism). The agonistic or antagonistic activity of raloxiffene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors. Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density and decreases fracture incidence.

Literature References

Ozmen B, Kirmaz C, Aydin K, Kafesciler SO, Guclu F, Hekimsoy Z. Influence of the selective oestrogen receptor modulator (raloxifene hydrochloride) on IL-6, TNF-alpha, TGF-beta1 and bone turnover markers in the treatment of postmenopausal osteoporosis. European Cytokine Network 2007 Sep 7;18(3):31-36

Fryar-Tita EB, Das JR, Davis JH, Desoto JA, Green S, Southerland WM, Bowen D Raloxifene and selective cell cycle specific agents: a case for the inclusion of raloxifene in current breast cancer treatment therapies. Anticancer Research 2007 May-Jun;27(3B):1393-9.

Cauley JA, Song J, Dowsett SA, Mershon JL, Cummings SR Risk factors for breast cancer in older women: the relative contribution of bone mineral density and other established risk factors. Breast Cancer Research and Treatment 2007 Apr;102(2):181-8

Lippman ME, Cummings SR, Disch DP, Mershon JL, Dowsett SA, Cauley JA, Martino S Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk. Clinical cancer research : an official journal of the American Association for Cancer Research 2006 Sep 1;12(17):5242-7

Siris ES, Harris ST, Eastell R, Zanchetta JR, Goemaere S, Diez-Perez A, Stock JL, Song J, Qu Y, Kulkarni PM, Siddhanti SR, Wong M, Cummings SR; Continuing Outcomes Relevant to Evista (CORE) Investigators Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2005 Sep;20(9):1514-24

Kawagoe J, Ohmichi M, Takahashi T, Ohshima C, Mabuchi S, Takahashi K, Igarashi H, Mori-Abe A, Saitoh M, Du B, Ohta T, Kimura A, Kyo S, Inoue M, Kurachi H Raloxifene inhibits estrogen-induced up-regulation of telomerase activity in a human breast cancer cell line. The Journal of Biological Chemistry 2003 Oct 31;278(44):43363-72

Kim HT, Kim BC, Kim IY, Mamura M, Seong DH, Jang JJ, Kim SJ Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells.The Journal of Biological Chemistry 2002 Sep 6;277(36):32510-5

Additional Information

For additional information regarding Evista or the treatment/prevention of osteoporosis and reduction of breast cancer risk in postmenopausal women, please visit the Evista web page.