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Raloxifene
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Recommendations for calcium and vitamin D intake:
60 mg PO once daily. Supplement with calcium and vitamin D if dietary intake is inadequate. During clinical trials, women with known osteoporosis had a median age of 67 years (range 31 to 80 years) and a median time since menopause of 19 years. In clinical trials for osteoporosis prophylaxis, women with low bone mineral density had a median age of 54 years and a median time since menopause of 5 years. LIMITATIONS OF USE: There is no indication for the use of raloxifene in premenopausal women; safety has not been established and use is not recommended.[29603] While raloxifene shows benefit in reducing vertebral fractures, it should generally not be considered for first line therapy as raloxifene does not reduce hip fracture or nonvertebral fractures and may be associated with serious harms, including thromboembolism. Per guidelines, first-line agents for osteoporosis and low bone mineral density include alendronate, risedronate, zoledronic acid, or denosumab. For postmenopausal patients with low bone mineral density in the spine but not in the hip, raloxifene may be considered for prevention of bone loss in postmenopausal women with an elevated risk of breast cancer and infrequent vasomotor symptoms.[66837] [67122] [67125] Patients at high risk of hip fracture who are taking raloxifene with the main goal of reducing their risk of breast cancer can reasonably have a bisphosphonate or denosumab added for hip fracture risk reduction; however, the risks and benefits of combined treatment are unknown.[66837]
60 mg PO once daily. The long-term effects and the recommended length of treatment are not known. LIMITATIONS OF USE: There is no indication for the use of raloxifene in premenopausal women; safety has not been established and use in premenopausal women is not recommended. Raloxifene is not indicated for the treatment of invasive breast cancer or for reducing the risk of recurrence. Raloxifene is also not indicated for reducing the risk of noninvasive breast cancer. There are no data available regarding the effect of raloxifene on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations regarding the drug's effectiveness in these women.[29603] In the MORE trial, postmenopausal women (age 31 to 80 years) with osteoporosis taking raloxifene experienced a reduction in the risk of breast cancer of 76% (relative risk 0.24, 95% CI 0.13 to 0.44) after 3 years of treatment. An extension of this trial, the CORE trial, continued to follow patients taking raloxifene for a total of 8 years. Patients taking raloxifene had a reduced risk of invasive breast cancer of 66% at 8 years (HR 0.34, 95% CI 0.22 to 0.5).[32138] Results of the STAR trial, which compared raloxifene to tamoxifen for the prevention of breast cancer, indicate that raloxifene is comparable to tamoxifen; both drugs decreased the risk of invasive breast cancer by approximately 50%. The RUTH trial also confirms the decreased risk of breast cancer with raloxifene therapy vs. placebo after 5 years (HR 0.56, 95% CI 0.38 to 0.83).[32460]
60 mg PO once daily.[26611]
Recommended Monitoring
60 mg/day PO.
60 mg/day PO.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
No dosage guidelines are available; however, patients may be at increased risk for side effects. Patients with cirrhosis have up to 2.5-fold higher serum levels of raloxifene than patients with normal hepatic function. Safety and efficacy have not been established in patients with hepatic impairment.
No dosage guidelines are available; however, raloxifene should be used with caution in patients with renal impairment. Safety and efficacy have not been established in patients with moderate to severe renal impairment.
† Off-label indication
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, it does not stimulate uterine tissue and behaves as an estrogen antagonist in the uterus. Raloxifene's pharmacologic effects make it a useful agent for the prevention of postmenopausal osteoporosis; although it is not useful for postmenopausal hot flashes. The effect of 60 mg/day on total-body bone mineral density is similar to that of estrogen/progestin HRT or alendronate 5 mg/day, but, the effect on bone mineral density of the lumbar spine may be less.[25061] Raloxifene has been shown to significantly decrease the incidence of vertebral fractures, but not other fractures, during clinical trials. According to the North American Menopause Society (NAMS), it may be considered for women who are at increased risk of vertebral fracture versus hip fracture.[67122] Raloxifene is also indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and postmenopausal women at high risk for breast cancer. Large clinical trials examining the long-term effects of raloxifene have been completed and include: the Raloxifene Use for the Heart (RUTH) study, to determine its effects on cardiovascular events and invasive breast cancer in women with established coronary heart disease (CHD) or at risk for CHD; the Multiple Outcomes of Raloxifene Evaluation (MORE), that evaluates effectiveness for osteoporosis and effect on the risk of cardiovascular events and breast cancer in postmenopausal women up to 80 years of age with osteoporosis; and the Study of Tamoxifen and Raloxifene (STAR), designed to compare efficacy in the prevention of breast cancer. Based on results from the MORE trial, raloxifene therapy for 4 years does not appear to significantly affect the risk of cardiovascular events overall, but does significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk.[27056] In results reported from the MORE trial among postmenopausal women, the risk of invasive breast cancer is decreased by 76% during 3 years, and by 72% after 4 years, of treatment with raloxifene relative to placebo.[27057] Results from the Continuing Outcomes Relevant to Evista (CORE) study (a 4-year extension of the MORE trial), indicate that 8 years of raloxifene therapy reduces the risk of invasive breast cancer by 66% (hazard ratio 0.34, 95% CI 0.22 to 0.5).[32138] It should be noted that findings from the CORE and MORE trials indicate that the risk of estrogen-receptor negative breast cancer is not reduced by raloxifene. The STAR study results confirm the findings of the MORE and CORE studies; four years of either tamoxifen or raloxifene reduces the risk of invasive breast cancer at a similar rate (by approximately 50%). A benefit of raloxifene over tamoxifen is a reduced rate of venous thromboembolism (RR 0.7, 95% CI 0.54 to 0.99); however, the risk of non-invasive breast cancer is reduced by tamoxifen, but not raloxifene. Furthermore, the risk of uterine cancer is reduced, although non-significantly, with raloxifene (RR 0.62, 95% CI 0.35 to 1.08).[32250] Results from the RUTH trial also confirm that raloxifene reduces the risk of invasive breast cancer (HR 0.56, 95% CI 0.38 to 0.83) relative to placebo; the mean baseline 5-year risk of breast cancer in the women participating in this study was 1.73%, with 41% of patients having a score of 1.66% or more. However, the risk of coronary events (death from coronary causes, myocardial infarction, or hospitalization for acute coronary syndrome) was not different between raloxifene or placebo in this population of women with existing or at increased risk of CHD. Additionally, the risk of fatal stroke and venous thromboembolism were increased in patients taking raloxifene (HR 1.49, 95% CI 1 to 2.24 for fatal stroke and HR 1.44, 95% CI 1.06 to 1.95).[32460] Raloxifene does appear to reduce the risk of invasive breast cancer; however, the benefits of breast cancer risk reduction have to be balanced with the increased risks of thromboembolic events in each individual patient.
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Hazardous Drugs Classification
During clinical trials, the most common treatment-related adverse event associated with use of raloxifene was hot flashes (7.8% to 28.7%). Hot flashes were usually reported within the first 6 months of treatment and were not different from placebo thereafter. In controlled clinical trials, drug discontinuation due to hot flashes was similar among patients receiving raloxifene (1.7%) and those receiving placebo (2.2%). Sweating or hyperhidrosis occurred in 2.5% to 3.1% of patients taking raloxifene vs. 1.7% to 2% of patients taking placebo.[29603]
In placebo-controlled clinical trials, raloxifene was associated with an increased risk of venous thromboembolism (VTE), defined as deep vein thrombosis, pulmonary embolism (PE) compared to placebo. An increased risk for and superficial thrombo-phlebitis also occurred. During an average of 2.6 years of drug exposure in patients taking raloxifene for the treatment of osteoporosis, VTE occurred in about 1 of 100 patients treated with raloxifene (HR 2.4, 95% CI 1.2 to 4.5). In patients with an increased risk for major coronary events (RUTH trial), VTE occurred in 2% of patients receiving raloxifene vs. 1.4% of patients taking placebo. The greatest risk occurs within the first 4 months of treatment. Of note, the increased risk of venous thromboembolism is similar in magnitude to that reported with hormone replacement therapy. The mechanisms by which raloxifene increases VTE is unknown. Unlike estrogens, raloxifene does not appear to enhance fibrinolysis. Varicose vein was reported in 2.2% of patients taking raloxifene vs. 1.5% of patients taking placebo in clinical trials. Adverse reactions reported very rarely since market introduction include retinal vein occlusion (retinal thrombosis) and death associated with VTE.[29603]
Raloxifene may increase the risk for death from stroke in at-risk patients. In the Raloxifene Use for The Heart (RUTH) trial of postmenopausal women with documented coronary artery disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene relative to placebo. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 vs. 15 per 10,000 women-years; hazard ratio 1.49; 95% CI, 1 to 2.24; p = 0.0499). There was no statistically significant difference between treatment groups in the overall incidence of stroke (4.9% for raloxifene vs. 4.4% for placebo). Raloxifene use had no significant effect on all-cause mortality.[29603] [32460] In the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial, the risk of stroke was found to be similar between tamoxifen and raloxifene, with annual rates of 1.39 per 1,000 patients taking tamoxifen and 1.33 per 1,000 patients taking raloxifene.[32250]
Cardiovascular related adverse events reported during clinical trials of raloxifene and occurring at rates higher than with placebo included chest pain (unspecified) (2.8% to 4%), syncope (2.3%), and peripheral edema (3.3% to 14.1%).[29603]
Arthralgia (10.7% to 15.5%) and muscle cramps, specifically leg cramps, were some of the most commonly reported treatment-related adverse events in patients taking raloxifene (5.9% to 12.1%) and occurring at an incidence greater than with placebo. Other reported musculoskeletal adverse events with raloxifene include myalgia (7.7%), arthritis (4%), and tendon disorder (3.6%).[29603]
Central nervous system reactions that have been reported during raloxifene clinical trials at rates higher than with placebo include headache (9.2%), migraine (2.4%), mental depression (6.4%), insomnia (5.5%), vertigo (4.1%), neuralgia or neuropathic pain (2.4%), and hypoesthesia (2.1%).[29603]
Gastrointestinal (GI) adverse events that have been reported during clinical trials of raloxifene at incidences higher than with placebo include nausea (9.7% to 24.6%), diarrhea (7.2%), dyspepsia (5.9%), vomiting (3.4% to 4.8%), flatulence (3.1%), abdominal pain (6.6%), cholelithiasis (3.3%), gastroenteritis (2.6%), and gastrointestinal disorder (3.3%).[29603]
Urogenital adverse reactions that have been reported during raloxifene clinical trials at rates higher than with placebo include vaginitis (4.3%), leukorrhea (3.3%), uterine disorder (3.3%), endometrial disorder (3.1%), and vaginal bleeding (2.5%). The incidence of vaginal bleeding is significantly lower in patients treated with raloxifene vs. those treated with hormone replacement therapy (6.2% for raloxifene vs. 64.2 to 88.5% for hormone replacement therapy). Although breast pain (mastalgia) has been reported in 4.4% of women treated with raloxifene for osteoporosis prevention, the incidence was significantly lower than the incidence in patients treated with hormone replacement therapy (29.7 to 37.5%); further, the incidence and severity of mastalgia was similar when comparing patients taking raloxifene to placebo.[29603] In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months in 831 women. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo.[25061] The incidence of endometrial cancer and ovarian cancer were similar between patients taking raloxifene and placebo.[29603]
Rash (unspecified) (5.5%) has been reported during clinical trials of raloxifene.[29603]
Weight gain (8.8%) has been reported during clinical trials of raloxifene.[29603]
Infectious and/or respiratory-related adverse reactions that have been reported during clinical trials of raloxifene and at incidences higher than placebo include infection (11% to 15.1%); examples of specific infections include sinusitis (7.9% to 10.3%), rhinitis (10.2%), bronchitis (9.5%), pharyngitis (5.3% to 7.6%), laryngitis (2.2%), influenza (13.5% to 14.6%), urinary tract infection (4%), conjunctivitis (2.2%), and cystitis (3.3% to 4.6%). Increased cough (6% to 9.3%) and fever (3.1% to 3.9%) have also been reported.[29603]
The coadministration of certain medications may lead to harm and require avoidance or therapy modification; review all drug interactions prior to concomitant use of other medications.
This medication is contraindicated in patients with a history of hypersensitivity to it or any of its components.
Raloxifene is contraindicated in individuals with an active or past history of venous thromboembolism, including deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis. Consider the risk-benefit balance in individuals at risk of thromboembolism for other reasons, such as congestive heart failure, superficial thrombophlebitis, active neoplastic disease, and thrombophilia. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy.[29603]
Discontinue raloxifene at least 72 hours prior to and during prolonged immobility (e.g., recovery from major surgery, prolonged bed rest) due to an increased risk for thromboembolic events independent of raloxifene therapy; resume treatment only after the individual is fully ambulatory. Additionally, advise individuals receiving raloxifene to move about periodically during prolonged travel.[29603]
Consider the benefits of therapy with raloxifene versus the risk of stroke in individuals at risk, including those with a history of cerebrovascular disease, atrial fibrillation, hypertension, or tobacco smoking. An increased risk of death due to stroke occurred in postmenopausal women with documented coronary artery disease or otherwise at increased risk for major coronary events.[29603]
Raloxifene is contraindicated in women during pregnancy. The safety of raloxifene in premenopausal women has not been established. Use in premenopausal women is not recommended due to concern of inadvertent drug exposure during pregnancy and the risk of fetal harm. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal studies have demonstrated a potential for fetal harm. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses greater than or equal to 0.1 mg/kg (0.04 times or more the human dose based on surface area, mg/m2), and hydrocephaly was observed in fetuses at doses greater than or equal to 10 mg/kg (4 times or more the human dose based on BSA). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses greater than or equal to 1 mg/kg (0.2 times or more the human dose based on BSA). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on BSA) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.[29603]
Monitor serum triglycerides in individuals with a history of hypertriglyceridemia during treatment with raloxifene. Limited data suggest that some women with a history of marked hypertriglyceridemia (greater than 5.6 mmol/L or greater than 500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene.[29603]
Raloxifene is not indicated for use in females of reproductive potential. There is no information on the presence of raloxifene in human milk, the effects on the breast-fed child, or the effects on milk production. However, based on mechanism of action, raloxifene may block the important functions that estrogen has in mammary tissue during breast-feeding.[29603]
The reproductive and developmental effects observed in animal studies are consistent with the estrogen receptor activity of raloxifene. In female animals, raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. Raloxifene also delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. It is unknown if reproductive risk or issues relating to infertility would occur in humans.[29603]
Mechanism of Action: Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors, which results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). 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. Raloxifene appears to act as an estrogen agonist in bone. 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). In postmenopausal women, raloxifene increases total-body BMD, including BMD of the lumbar spine, hip, and femoral neck, and decreases fracture incidence.
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.
Revision Date: 07/03/2025, 05:36:01 AMRaloxifene is administered orally. Both raloxifene and its monoglucuronide conjugates are highly (95%) bound to plasma proteins, with raloxifene binding to both albumin and alpha-1-acid glycoprotein; raloxifene does not bind to sex-steroid binding globulin. Raloxifene exhibits high within-subject variability (CV, 30%) of most pharmacokinetic parameters. The apparent volume of distribution is 2,348 L/kg (CV, 52%) after a single dose, which is not dose dependent; the Vd increases to 2,853 L/kg (CV, 56%) with multiple doses. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates including raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4'-diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways. Less than 1% of total radiolabeled material in plasma consists of unconjugated raloxifene. The terminal log-linear portions of plasma concentration curves for raloxifene and the glucuronides are generally parallel, which is consistent with the interconversion of raloxifene and the glucuronide metabolites. The apparent oral clearance of raloxifene is 44.1 L/kg x hr after a single dose (CV, 46%); however, clearance ranges from 40 to 60 L/kg x hr with chronic dosing. After IV administration, raloxifene clearance approximates hepatic blood flow. The plasma elimination half-life is 27.7 hours after a single oral dose, which is prolonged to 32.5 hours after multiple doses due to interconversion of raloxifene and its glucuronide conjugates by reversible systemic metabolism and enterohepatic cycling. Raloxifene is primarily excreted in the feces, with less than 0.2% excreted unchanged in the urine; less than 6% of a dose is eliminated in urine as glucuronide conjugates.[29603]
Affected cytochrome P450 isoenzymes and drug transporters: None
Raloxifene is rapidly absorbed after oral administration, with approximately 60% of an oral dose absorbed; however, presystemic glucuronide conjugation is extensive. The absolute bioavailability of raloxifene is 2%. The Cmax of raloxifene was 0.5 ng/mL (CV, 52%) after a single dose and 1.36 ng/mL (CV, 37%) after multiple doses when normalized for dose (mg/kg); the raloxifene AUC normalized for dose (mg/kg) was 27.2 ng x hr/mL (CV, 44%) and 24.2 ng x hr/mL (CV, 36%), respectively. The AUC of raloxifene increases in a slightly less than dose-proportional manner (30 to 150 mg). The time to reach the average Cmax and bioavailability (Tmax) are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. Administration with a high-fat meal increases the Cmax of raloxifene by 28% and the AUC of raloxifene by 16%; however, this is not a clinically meaningful increase in systemic exposure.[29603]
Plasma concentrations were increased by approximately 100% and the apparent clearance of raloxifene after a single dose was reduced by 56% in patients with mild hepatic impairment (Child-Pugh class A; total bilirubin 0.6 to 2 mg/dL) compared to subjects with normal hepatic function; plasma concentrations correlated with total bilirubin concentrations. The half-life of raloxifene was not altered in patients with mild hepatic impairment. The pharmacokinetics of raloxifene have not been studied in patients with moderate to severe hepatic impairment. The safety and efficacy of raloxifene have not been established in patients with hepatic impairment.[29603]
Raloxifene concentrations were similar in women with mild renal impairment and normal renal function in osteoporosis treatment and prevention trials. The AUC of raloxifene was 122% higher in men with moderate to severe renal impairment (CrCl 50 mL/min or less) compared to healthy volunteers (CrCl greater than 80 mL/min) after a single dose.[29603]
The pharmacokinetics of raloxifene have not been evaluated in pediatric patients.[29603]
Age (42 to 84 years) did not affect the pharmacokinetics of raloxifene.[29603]
Raloxifene exposure and oral clearance are not significantly different between age-matched female and male volunteers when normalized for lean body weight.[29603]
There were no discernible differences in raloxifene plasma concentrations due to race in the osteoporosis prevention trials.[29603]
Raloxifene is contraindicated in women during pregnancy. The safety of raloxifene in premenopausal women has not been established. Use in premenopausal women is not recommended due to concern of inadvertent drug exposure during pregnancy and the risk of fetal harm. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal studies have demonstrated a potential for fetal harm. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses greater than or equal to 0.1 mg/kg (0.04 times or more the human dose based on surface area, mg/m2), and hydrocephaly was observed in fetuses at doses greater than or equal to 10 mg/kg (4 times or more the human dose based on BSA). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses greater than or equal to 1 mg/kg (0.2 times or more the human dose based on BSA). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on BSA) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.[29603]
Raloxifene is not indicated for use in females of reproductive potential. There is no information on the presence of raloxifene in human milk, the effects on the breast-fed child, or the effects on milk production. However, based on mechanism of action, raloxifene may block the important functions that estrogen has in mammary tissue during breast-feeding.[29603]
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