Raloxifene (Evista®)
Raloxifene
Brand Name: Evista®
Classification:
Hormones and Hormone Modifiers - Selective Estrogen-Receptor Modifiers (SERMs)
Description: Raloxifene is a selective estrogen receptor modulator (SERM) of the benzothiophene class. Similar to tamoxifen, raloxifene produces estrogen-like effects on bone and lipid metabolism, while antagonizing the effects of estrogen on mammary tissue. However, unlike estrogen or tamoxifen, raloxifene does not stimulate uterine tissue and behaves as an estrogen antagonist in the uterus. The pharmacologic effects of raloxifene make it a useful agent for the prevention of postmenopausal osteoporosis; although raloxifene is not useful for hot flashes in postmenopausal women. The effect of raloxifene 60 mg/day on total-body bone mineral density is similar to that of estrogen/progestin HRT or alendronate 5 mg/day, however, the effect on bone mineral density of the lumbar spine may be less with raloxifene than with these other agents. Large clinical trials examining the long-term effects of raloxifene include the Raloxifene Use for the Heart (RUTH) study, the Multiple Outcomes of Raloxifene Evaluation (MORE) that evaluates effectiveness for osteoporosis and the effect of raloxifene therapy on the risk of cardiovascular events and breast cancer in postmenopausal women up to 80 years of age, and the Study of Tamoxifen and Raloxifene (STAR) study that is designed to compare efficacy in the prevention of breast cancer. Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events overall in the MORE trial, but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. The effectiveness of raloxifene in reducing the risk of breast cancer has not been established and is under investigation. In results reported from the MORE trial among postmenopausal women, the risk of invasive breast cancer was decreased by 76% during 3 years of treament with raloxifene. Longer term data is needed from the MORE trial (i.e, results at 5 years) and the STAR trial to determine the role of raloxifene in breast cancer chemoprevention and the effects of the drug on cardiovascular health. Raloxifene received final FDA approval for the prevention of osteoporosis in December 1997.
Mechanism of Action: Raloxifene reduces resorption of bone and increases bone mineral density in postmenopausal women without stimulating the endometrium or breast tissue. Decreases in circulating estrogen after oophorectomy or menopause lead to enhanced bone resorption. Bone loss is initially rapid because the compensatory increase in bone formation is inadequate to offset resorptive losses. The effects of raloxifene on bone are manifested as reductions in serum and urine concentrations of bone turnover markers, decreased bone resorption, and increases in bone mineral density (BMD). These effects are mediated through binding of raloxifene to estrogen receptors. The estrogen receptor can regulate gene expression by at least two distinct pathways, which are ligand-, tissue-, and/or gene-specific. Binding of raloxifene to the estrogen receptor results in differential expression of multiple estrogen-regulated genes in different tissues. Similar to tamoxifen, raloxifene produces estrogen-like effects on bone while antagonizing the effects of estrogen on mammary tissue. However, while tamoxifen stimulates uterine tissue, raloxifene produces a nearly complete blockade of uterotrophic responses to estrogen and can antagonize the uterine stimulatory effect of tamoxifen.
In postmenopausal women, raloxifene increases total-body BMD, including BMD of the lumbar spine, hip, and femoral neck. Similar to estrogen replacement therapy, raloxifene also decreases total and low-density lipoprotein cholesterol, and lipoprotein(a) concentrations. However, estrogen increases high-density lipoprotein cholesterol and triglycerides, while raloxifene has no effect on these lipoproteins. Unlike estrogen, raloxifene does not stimulate the endometrium in postmenopausal women with an intact uterus.
Evista Tablets(Tab 60 mg) 
Pharmacokinetics: Raloxifene is administered orally. Absorption is rapid after an oral dose. Although roughly 60% of a dose is absorbed, presystemic glucuronide conjugation is extensive. Thus, absolute bioavailability is only about 2%. Raloxifene and its glucuronide metabolites undergo enterohepatic cycling which affects bioavailability and time to peak plasma concentration. A high-fat meal increases the AUC and Cmax of raloxifene by 16% and 28%, respectively; however, these increases are not considered clinically significant. In patients with cirrhosis (serum bilirubin 0.6-2 mg/dl), plasma raloxifene concentrations are approximately 2.5 times higher than in patients without hepatic dysfunction. Raloxifene has a large volume of distribution (2348 L/kg); the parent drug and the monoglucuronide conjugates are highly bound to plasma proteins. Raloxifene binds to both albumin and alpha1-acid glycoprotein. It does not bind to sex steroid binding globulin. Raloxifene undergoes extensive first-pass metabolism to the following glucuronide conjugates: raloxifene-4’-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4’-diglucuronide. Because no other metabolites have been identified, it is believed that raloxifene is not metabolized by cytochrome P450 pathways. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling. Raloxifene is excreted primarily in feces. Less than 0.2% is excreted unchanged in urine and less than 6% is eliminated in urine as glucuronide conjugates. The plasma elimination half-life of raloxifene is highly variable. Mean elimination half-life after multiple oral doses is 32.5 hours (range: 15.8-86.6 hours). The pharmacokinetic disposition of raloxifene is similar among young adults, the elderly, and patients with impaired renal function (i.e., CrCl as low as 23 ml/min).
References
. Delmas PD, Bjarnason NH, Mitlak BH et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7.
. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in postmenopausal women four year results from the MORE (Multiple Outcomes of Raloxifene Evalulation) randomized trial. JAMA 2002;287:847-57.
. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women results from the MORE randomized trial. JAMA 1999;281:2189-97.
[ Revised 7/27/2004 5:00:00 PM ]
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