, Volume 68, Issue 14, pp 2059-2083

Raloxifene

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Summary

Abstract

Raloxifene (Evista®) is a second-generation selective estrogen receptor modulator (SERM) that functions as an estrogen antagonist on breast and uterine tissues, and an estrogen agonist on bone. It is available in many countries worldwide for the treatment and prevention of osteoporosis in postmenopausal women, and has also been approved in the US for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women at increased risk of invasive breast cancer.

Raloxifene reduces the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer and in postmenopausal women with osteoporosis. In addition, it is a well established agent for the prevention and treatment of osteoporosis. There was no significant difference between raloxifene and tamoxifen in the reduction in the risk of invasive breast cancer achieved in postmenopausal women at high risk of such cancer. Raloxifene was associated with an increased, albeit rare, risk of venous thromboembolism across several placebo-controlled trials and an increased risk of fatal stroke in one placebo-controlled trial in postmenopausal woman at increased risk for major coronary events. However, raloxifene was associated with a lower risk of venous thromboembolic events and cataracts than tamoxifen in a head-to-head trial. The choice of chemoprevention agent must consider a risk-benefit assessment for each individual patient. In this context, raloxifene is a valuable option for the prevention of invasive breast cancer in postmenopausal women with osteoporosis or at high risk of invasive breast cancer.

Pharmacological Properties

Raloxifene is a benzothiophene SERM; it competes with estrogen at estrogen receptors (ERs) and acts as an estrogen agonist in bone, and an estrogen antagonist in uterine and breast tissues. The mechanism of action of raloxifene is not yet fully understood. Raloxifene inhibited the proliferation of breast cancer cells in vitro and did not increase mammographic breast density or stimulate the endometrium in postmenopausal women. The drug had positive effects on markers of breast cancer risk, including insulin-like growth factor-I and sex hormone-binding globulin, in postmenopausal women with breast cancer. In addition, raloxifene decreased markers of bone turnover, increased/maintained bone mineral density and maintained bone architecture in postmenopausal women.

Following oral administration, raloxifene is absorbed rapidly. It undergoes extensive first-pass glucuronidation and enterohepatic cycling, and its absolute bioavailability is 2%. Raloxifene is extensively distributed in the body and is highly bound to plasma proteins. Raloxifene does not appear to be metabolized by the cytochrome P450 system, as no other metabolites have been detected. The mean elimination half-life of raloxifene was 27.7 hours and excretion of raloxifene occurred primarily via the faeces.

Therapeutic Efficacy

The efficacy of raloxifene in preventing invasive breast cancer was examined in several large, well designed trials: the placebo-controlled 4-year MORE trial in postmenopausal women with osteoporosis (and its 4-year extension, the CORE trial); the placebo-controlled RUTH trial in postmenopausal women at increased risk for major coronary events (median duration of follow-up of 5.6 years); and the STAR trial, which compared raloxifene with tamoxifen in postmenopausal women at high risk of invasive breast cancer (median follow-up 4.3 years). The primary endpoint in the MORE trial was the incidence of vertebral fractures, with the incidence of breast cancer being a secondary endpoint. The incidence of invasive breast cancer was the primary endpoint in the CORE, RUTH and STAR trials, with the RUTH trial having a composite coronary endpoint as the co-primary endpoint.

In the MORE, CORE and RUTH trials, the incidence of invasive breast cancer was significantly lower in patients receiving raloxifene than in those receiving placebo. The incidence of ER-positive invasive breast cancer was significantly lower with raloxifene than with placebo in these trials, although there were no significant between-group differences in the incidence of ER-negative invasive breast cancer or noninvasive breast cancer. Significantly fewer raloxifene than placebo recipients experienced new vertebral fractures in the MORE and RUTH trials. There was no significant difference in the incidence of the composite coronary endpoint between raloxifene and placebo recipients in the RUTH trial.

In the STAR trial, there was no significant difference between raloxifene and tamoxifen in the incidence of invasive breast cancer. The between-group differences in the incidences of ER-positive or ER-negative invasive breast cancer, noninvasive breast cancer or osteoporotic fractures were also not significant. Health-related quality of life in the STAR trial was not affected by treatment overall, although effects on sexual functioning favoured tamoxifen.

Tolerability

Common adverse events associated with raloxifene were hot flushes (flashes), peripheral oedema and leg cramps. Thromboembolic events were rare but serious events that occurred in significantly more raloxifene than placebo recipients in the MORE and RUTH trials, and there was an increased risk of fatal stroke with raloxifene versus placebo in the RUTH trial.

When compared with tamoxifen, raloxifene recipients had significantly lower incidences of thromboembolic events and cataracts, and less severe leg cramps and vasomotor, gynaecological and bladder symptoms. Musculoskeletal symptoms, dyspareunia and weight gain were more severe in raloxifene recipients; however, the severity of all patient-reported symptoms was generally low. There was no significant difference between tamoxifen and raloxifene recipients in the incidence of endometrial cancer in the STAR trial, although the ability to detect a difference was limited by the significantly higher number of hysterectomies (not related to uterine cancer) performed on tamoxifen recipients during follow-up.

Various sections of the manuscript reviewed by: T.B. Bevers, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; V.C. Jordan, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; V.G. Vogel, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; D.L. Wickerham, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, Pennsylvania, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘raloxifene’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘raloxifene’ and (‘invasive breast cancer’ or ‘breast cancer’). Searches were last updated 1 September 2008.
Selection: Studies in postmenopausal women who received raloxifene for prevention of breast cancer. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Raloxifene, invasive breast cancer, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.