Evista (raloxifene hydrochloride)
The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
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.