AHFS Class:

• Estrogen Agonists-Antagonists 68:16.12

Generic Name(s):

• Raloxifene Hydrochloride

Raloxifene hydrochloride, a nonsteroidal benzothiophene derivative, is an estrogen agonist-antagonist.1,2,3,13,14,15,16,17,55,69,70

Osteoporosis

Raloxifene is used for the prevention and treatment of osteoporosis in postmenopausal women.1,108

Osteoporosis, a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with consequent increased bone fragility and susceptibility to fracture, is observed in a large proportion of postmenopausal women.1,19,20,78,79,80,81,82 Adult women have less bone mass than men at all ages, and decreased production of estrogen at menopause is associated with accelerated bone loss, particularly from the lumbar spine, for about 5 years, during which time skeletal mass loss averages 3% per year.78,79,80,81,82,83 While the risk of postmenopausal osteoporosis cannot be quantified by a single clinical finding or test result, many risk factors have been identified, with the probability of developing osteoporosis increasing with multiple risk factors.1,20,78,79,80,81,82,105,106 Risk factors for postmenopausal osteoporosis and related fractures include early menopause, decreased bone mineral density (BMD), low body mass index (BMI), previous fracture or family history of fracture/osteoporosis, excessive alcohol intake, smoking, inadequate physical activity, low calcium and vitamin D intake, certain drugs (e.g., glucocorticoids), and medical conditions or diseases (e.g., rheumatoid arthritis, diabetes mellitus, Cushing syndrome, hyperparathyroidism).105,106

In addition to adequate intake of calcium/vitamin D and other lifestyle modifications (e.g., exercise, avoidance of excessive alcohol and tobacco use), experts recommend that pharmacologic therapy for osteoporosis be considered in postmenopausal women who are at high risk of fractures (generally those who have experienced a previous hip or vertebral fracture or who have low BMD);105,106 pharmacologic therapy also may be considered in postmenopausal women who have low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients.105 When selecting an appropriate pharmacologic agent, use of a drug with proven antifracture efficacy is recommended.106 Experts generally recommend raloxifene as a second- or third-line agent after other therapies (e.g., bisphosphonates) have been attempted.105,106 Choice of therapy should be individualized based on the potential benefits (with respect to fracture risk reduction) and adverse effects of therapy as well as patient preferences, comorbidities, and risk factors.105,106 For additional information on the prevention and treatment of osteoporosis,

Prevention in Postmenopausal Women

Raloxifene is used for the prevention of osteoporosis in postmenopausal women; supplemental calcium and/or vitamin D should be used concomitantly if daily dietary intake is considered inadequate.1,2,3,4,5,6,7,16,17,23,55,69,108 The goal of preventive therapy is preservation of bone mass and a resultant decrease in fracture risk.20,78,79,80,81,82,87 Unlike estrogens, raloxifene is not effective in relieving vasomotor symptoms (hot flushes [ flashes]) associated with estrogen deficiency.1,2,23,29,69,88 The efficacy of raloxifene in preventing other forms of osteoporosis (e.g., drug [ such as corticosteroid]-induced) remains to be established.91,96

Raloxifene has been evaluated for the prevention of osteoporosis in postmenopausal women in 3 multinational (North American trial, European trial, International trial), randomized, placebo-controlled, double-blind studies that included 1764 women (median age: 54 years; median time since menopause: 5 years; 93.5% white; all women in the International trial had undergone hysterectomy; 12 or 19% of women in the European or North American trials, respectively, had undergone hysterectomy) with normal or low (osteopenia) BMD values (mean lumbar spine BMD value 0.74-1 standard deviations below the premenopausal mean).1,2,55,69,96 All women received 400-600 mg of elemental calcium daily in addition to their usual dietary calcium intake.1,2 In these studies, therapy with raloxifene hydrochloride 60 mg daily increased BMD, as determined by dual-energy radiographic absorption (DXA) measurements, in the lumbar spine, hip, and total body.1,2,69 While women receiving placebo (i.e., calcium) lost approximately 1% of BMD at 24 months, substantial increases in BMD were apparent at 12 months following initiation of raloxifene therapy and were maintained at 24 months.1,2,69 Increases in total body BMD of 1.3-2% compared with placebo (i.e., calcium) have been reported in raloxifene-treated women.1,2 In North American or European postmenopausal women receiving raloxifene hydrochloride 60 mg daily for 24 months, the increase in BMD (expressed as mean % increase versus placebo) was 2-2.4% for total hip, 2.1-2.5% for femoral neck, 2.2-2.7% for trochanter, 2.3-2.4% for intertrochanter, and 2-2.4% for lumbar spine.1,2 In women receiving raloxifene hydrochloride 60 mg daily who had undergone hysterectomy (the International trial), the increase in BMD (expressed as mean % increase versus placebo) was 1.3% for total hip, trochanter, and intertrochanter; 1.6% for femoral neck; and 1.8% for lumbar spine.1 The effect of raloxifene therapy for longer than 2 years is being investigated in ongoing studies.1,69 Whether increases in BMD are maintained following withdrawal of raloxifene has not been established.91 The effect of raloxifene therapy on forearm BMD remains to be determined.1 While raloxifene prevented bone loss at the ultradistal radius in one study (European trial), a protective effect at this site was not documented in another study (North American trial).1

The effect of raloxifene on BMD versus estrogens or alendronate has been evaluated in several clinical studies.2,55,69,87,116 In one comparative study, therapy with conjugated estrogens 0.625 mg daily for 6 months was associated with substantially greater increases in BMD than therapy with raloxifene.116 Based on historical comparisons, the effect of raloxifene on hip BMD appears to be slightly less than that of estrogen/progestin or alendronate, and the effect of raloxifene on lumbar spine BMD appears to be about half that of estrogen/progestin or alendronate.2,44,55 In osteoporosis prevention studies that evaluated raloxifene (European trial), various estrogen/progestin combinations (HRT) (Early Postmenopausal Intervention Cohort Study), or alendronate therapy (Early Postmenopausal Intervention Cohort Study) for 24 months, raloxifene hydrochloride therapy (60 mg daily) was associated with 1.6% increases in hip BMD compared with baseline, HRT was associated with 1.8-3.2% increases, and alendronate (5 mg daily) therapy was associated with 1.3-1.9% increases.2,44,55 In these studies, raloxifene, HRT, or alendronate was associated with increases in BMD of lumbar spine of 1.6%, 4-5.1%, or 2.9-3.5%, respectively, compared with baseline.2,44,55 In a limited number of healthy postmenopausal women, administration of tamoxifen 20 mg daily for 24 months was associated with an increase in lumbar spine BMD compared with baseline of 1.4%.42

While the exact role of raloxifene in the prevention of osteoporosis relative to other available agents (e.g., estrogens, alendronate, risedronate) remains to be clearly determined, advantages of raloxifene include a better adverse effect profile than that of estrogens (with or without progestin).2,5,6,7,16,17,40,41,69,88,89,91,96,110 In addition, raloxifene may be especially useful in patients who are unable or unwilling to comply with the recommended regimen for oral administration of alendronate.40,69,91 While estrogen replacement therapy is effective for the prevention of osteoporosis in women, such therapy is associated with a number of adverse effects and the proportion of postmenopausal women who take estrogens for prolonged periods of time is low.2,5,6,7,16,17,40,41,69,78,87 Because raloxifene appears to have a more favorable adverse effect profile than estrogen or estrogen/progestin therapy, long-term compliance with raloxifene may be better than that with estrogens.2,5,6,7,16,17,40,41,69 However, clinical experience with raloxifene is limited compared with estrogen replacement therapy, and the effect of raloxifene on fracture rates has not been established.2,5,6,7,16,17,40,41,69 The role of raloxifene versus alendronate also has not been established.40 The choice of alendronate, estrogen, raloxifene, or risedronate for the prevention of postmenopausal osteoporosis should be individualized, taking into account differences in tolerability and safety, and individual preference.2,5,6,7,16,17,40,41,44,87,91,96,110,111

The optimal timing for initiation of preventive therapy for osteoporosis, including that with raloxifene, and the optimal duration of such therapy remain to be established.1,2,40,85,86,87 Although raloxifene preventive therapy was initiated at a median of 5 years postmenopause in clinical trials,1,2 experience with estrogen replacement therapy suggests that the protective effect may be greatest if the drug is initiated soon after menopause and continued into late life or indefinitely.84,85,86,87,91,96 If preventive therapy is not initiated soon after menopause, some benefit also may be likely with delayed initiation.85,91,96 In general, exercise and adequate calcium and vitamin D intake should be encouraged for all women.40,78,79,80,81,82,83,87 Whether additional preventive therapy generally should be offered to all women or just recommended for selected women at highest risk of developing osteoporosis remains to be established.86,87

Treatment in Postmenopausal Women

Raloxifene is used for the treatment of osteoporosis in postmenopausal women.1,53,69,98,99,108 While recent evidence indicates that raloxifene reduces the risk of vertebral fracture in women with osteoporosis,1,98,99 experience with the drug is limited and efficacy of raloxifene in the treatment of osteoporosis compared with that of estrogens or alendronate remains to be determined.99,103,104 The role of raloxifene in the treatment of osteoporosis may be determined by the effect of the drug on breast cancer.1,99

The effects of raloxifene on BMD and fracture incidence have been evaluated in a 3-year, multinational, randomized, double-blind study that included 7705 postmenopausal women (median age: 67 years; median time since menopause: 19 years) with osteoporosis (vertebral or hip BMD values at least 2.5 standard deviations below premenopausal mean values without baseline vertebral fractures or one or more vertebral fractures).1,98 All women received 500 mg of elemental calcium daily and 10-15 mcg (400-600 units) of cholecalciferol daily in addition to their usual calcium and vitamin D intake.1,98 In this study, therapy with raloxifene increased BMD (as determined by dual-energy radiographic absorption [DXA] measurements) of the spine, hip, and total body, and reduced the risk of vertebral fracture (as determined radiographically).1,98,99

In women receiving raloxifene 60 mg daily for 24 months, the increase in BMD (expressed as a mean percent increase versus placebo) was 2.2% for ultradistal radius, 0.9% for distal radius, and 1.1% for total body.1 In women receiving raloxifene 60 mg daily for 36 months, the increase in BMD was 2.6% for lumbar spine and 2.1% for femoral neck.1,98 In this study, women receiving raloxifene had fewer new vertebral fractures regardless of vertebral fracture status at the beginning of the study.1,98,99 In women without baseline vertebral fractures, radiographic evaluation at study completion revealed one or more new vertebral fractures in 4.3% of placebo-treated women and in 1.9% of raloxifene-treated women (relative risk reduction 55%).1,98 In women with one or more baseline fractures, radiographic evaluation at study completion revealed one or more new fractures in 20.2% of placebo-treated women and in 14.1% of women receiving raloxifene hydrochloride 60 mg daily (relative risk reduction 30%).1,98 In women with one or more baseline fractures, the incidence of new fractures was 10.7% in women receiving raloxifene hydrochloride 120 mg daily.98 Fewer raloxifene-treated women (1.8%) experienced one or more new symptomatic vertebral fractures than placebo-treated women (3.1%).1 Differences in the reduction in vertebral fracture risk associated with raloxifene therapy based on age, baseline femoral neck or lumbar spine BMD, prior hormone replacement therapy, or prior hysterectomy have not been observed in this study.98 A reduction in nonspinal fractures was not observed in raloxifene-treated women at month 36.98,99

Use in Premenopausal Women

Safety and efficacy of raloxifene in premenopausal women have not been established,1 and the role, if any, of the drug in the prevention or treatment of osteoporosis in such women remains to be determined.91

Glucocorticoid-induced Osteoporosis

Raloxifene has been used for the treatment and prevention of glucocorticoid-induced osteoporosis†.622

The American College of Rheumatology (ACR) recommends optimizing calcium and vitamin D intake and lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) in all patients receiving long-term glucocorticoid therapy; in addition, pharmacologic therapy with an oral bisphosphonate is recommended in patients who are considered to be at moderate-to-high risk of fracture.622 Oral bisphosphonates generally are preferred because of their demonstrated antifracture benefits, safety, and cost; experts state that raloxifene may be used in postmenopausal women if no other therapy is available.622

Breast Cancer

Raloxifene is used to reduce the incidence of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for developing invasive breast cancer.1 Raloxifene should not be used to reduce the risk of breast cancer in premenopausal women †.113,117

Raloxifene is not indicated for the treatment of breast cancer or to reduce the risk of recurrence of breast cancer.1 Raloxifene is not indicated for reduction in the risk of noninvasive breast cancer.1

Reduction in the Incidence of Breast Cancer in Women with Osteoporosis

Raloxifene is used to reduce the incidence of invasive breast cancer in postmenopausal women with osteoporosis.1 Findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) study, a double-blind study that evaluated effects of raloxifene on fracture incidence (primary end point) and incidence of breast cancer (secondary end point) in postmenopausal women with osteoporosis, provided the first evidence of possible breast cancer risk reduction effects of raloxifene.93,100 Results from the 4-year MORE study showed a 72 and 84% reduction in the incidence of newly diagnosed invasive breast cancer and estrogen receptor (ER)-positive breast cancer, respectively, in women receiving raloxifene compared with those receiving placebo.100 The Continuing Outcomes Relevant to Evista (CORE) study investigated the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in a subset of the MORE cohort who agreed to continue therapy.114 During the 8 years of the MORE and CORE study, the incidence of invasive breast cancer and ER-positive breast cancer was reduced by 66 and 76%, respectively, in those receiving raloxifene compared with those receiving placebo.114 The incidence of noninvasive breast cancer in women receiving raloxifene was similar to that in women receiving placebo.1

Reduction in the Incidence of Breast Cancer in Women at High Risk

Raloxifene is used to reduce the incidence of invasive breast cancer in postmenopausal women at high risk for developing the disease.1

Experts consider use of raloxifene an option in postmenopausal women 35 years of age or older who are considered at high risk for developing breast cancer (i.e., a 5-year projected risk of 1.67% or greater based on the calculated score derived from the Gail risk model) to reduce the risk of invasive breast cancer.117,118,122,123 Additionally, experts consider use of raloxifene an option to reduce the risk of invasive breast cancer in postmenopausal women 35 years of age or older with a history of lobular carcinoma in situ (LCIS), since these women are at increased risk for developing invasive breast cancer in both the affected and contralateral breast. 117,118,122,123

The effects of raloxifene versus tamoxifen on reducing the incidence of breast cancer were evaluated in a double-blind, randomized, phase 3 study (Study of Tamoxifen and Raloxifene [STAR]; also known as the National Surgical Adjuvant Breast and Bowel Project [NSABP] P-2 study).1,109,113,121 This study enrolled postmenopausal women at least 35 years of age who were at high risk for developing breast cancer.1,109,113 Breast cancer risk was determined using the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool based on a statistical model (the Gail model).119 High risk was defined as a 5-year projected breast cancer risk score of 1.67% or greater, calculated using the NCI (or Gail) assessment tool. 113 Additionally, postmenopausal women 35 years of age or older with a history of LCIS, whose only prior treatment included local excision, were eligible to participate in the study.113 Patients enrolled in the STAR study were randomized to receive either tamoxifen (20 mg daily) or raloxifene (60 mg daily) for a maximum of 5 years.113

Analysis of data from the STAR study at an average follow-up of approximately 4 years (47 months) showed that raloxifene and tamoxifen were equivalent in efficacy in lowering the risk of invasive breast cancer (4.3 cases per 1000 women in the tamoxifen group versus 4.41 cases per 1000 women in the raloxifene group; risk ratio of 1.02).113,121,123 Although the comparison did not reach statistical significance, there were fewer cases of noninvasive breast cancer in women receiving tamoxifen than in those receiving raloxifene (1.51 per 1000 in the tamoxifen group versus 2.11 per 1000 in the raloxifene group; risk ratio of 1.4).113,123 In contrast to these findings, longer-term follow-up (approximately 7 years) showed that tamoxifen had a greater effect than raloxifene in lowering the risk of invasive breast cancer, while the between-treatment difference in risk of noninvasive breast cancer was smaller than that observed at the time of the initial analysis.121,123 The updated analysis showed a 24% reduction in raloxifene efficacy in lowering the risk of invasive breast cancer compared with tamoxifen.121 Although raloxifene remained as effective as tamoxifen in lowering the risk of invasive breast cancer in women with LCIS (risk ratio of 1.13), the drug was less effective than tamoxifen in women with atypical hyperplasia (risk ratio of 1.48).123 Noninvasive breast cancer was reported slightly (risk ratio of 1.22), but not significantly, more frequently in those receiving raloxifene compared with those receiving tamoxifen at approximately 7 years' follow-up.121,123

In the STAR study, use of raloxifene was associated with a lower risk of thromboembolic events than use of tamoxifen, but rates of myocardial infarction, severe angina, or acute ischemic syndrome did not differ between the raloxifene and tamoxifen groups.113 Rates of fracture were essentially identical in the raloxifene and tamoxifen groups.113 Fewer cataracts were reported in the raloxifene group than in the tamoxifen group.113 Between-treatment differences in adverse effects mostly remained similar over approximately 7 years' follow-up.121 Based on patient-reported symptoms and quality of life assessments performed during the STAR study, there were no differences in overall physical, mental health, or depressive symptoms among women receiving either raloxifene or tamoxifen.113,120 However, women receiving raloxifene reported more musculoskeletal problems, dyspareunia (painful intercourse), and weight gain; women receiving tamoxifen reported more bladder-control (e.g., urinary incontinence) problems, gynecologic problems, and leg cramps.120 At the time of the initial analysis, fewer cases of endometrial cancer were reported in women receiving raloxifene compared with tamoxifen, but the difference was not statistically significant; however, an increase in the risk of endometrial cancer and endometrial hyperplasia was reported in patients receiving tamoxifen compared with those receiving raloxifene at approximately 7 years.113,118,121,123

The effect of raloxifene on the reduction in breast cancer incidence in women with BRCA1 or BRCA2 genetic mutations has not been established.1 Additionally, the effect of raloxifene (or tamoxifen) has not been studied in women with a history of exposure to thoracic radiation, which is considered a possible risk factor for breast cancer.118

Reduction in the Incidence of Breast Cancer in Women at Increased Risk of Coronary Events

The effect of raloxifene on the incidence of coronary events and invasive breast cancer was evaluated in postmenopausal women with coronary heart disease or increased risk for coronary heart disease (Raloxifene Use for the Heart; RUTH).1,115 Results from the 5-year RUTH study showed a 44 and 55% reduction in the incidence of newly diagnosed invasive breast cancer and estrogen receptor (ER)-positive breast cancer, respectively, in women receiving raloxifene compared with those receiving placebo.1,115 Treatment with raloxifene did not affect the risk of coronary events; an increased risk of venous thromboembolic events and fatal stroke was observed in women receiving raloxifene.115

Administration

Raloxifene is administered orally as a single daily dose.1,2,55 The manufacturer states that the drug may be taken without regard to meals or time of day.1,55 Raloxifene may be administered concomitantly with calcium carbonate or aluminum and magnesium hydroxide-containing antacids.1

Dosage

Dosage of raloxifene hydrochloride is expressed in terms of the hydrochloride.1 Raloxifene hydrochloride 60 mg contains 55.71 mg of raloxifene.1

Patients receiving raloxifene for prevention or treatment of osteoporosis should receive supplemental calcium and/or vitamin D if their daily dietary intake is inadequate.1

Osteoporosis

Prevention in Postmenopausal Women

For the prevention of osteoporosis in postmenopausal women, the recommended dosage of raloxifene hydrochloride is 60 mg once daily.1,2,55

Treatment in Postmenopausal Women

For the treatment of osteoporosis in postmenopausal women, the recommended dosage of raloxifene hydrochloride is 60 mg once daily.1,98

Breast Cancer

Reduction in the Incidence of Breast Cancer

To reduce the incidence of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for developing invasive breast cancer, the recommended dosage of raloxifene hydrochloride is 60 mg once daily.1 The American Society of Clinical Oncology (ASCO) recommends a treatment duration of 5 years.117,122 If a patient is receiving raloxifene as treatment for osteoporosis, for which breast cancer reduction is a secondary goal, ASCO suggests that the treatment duration may be extended beyond 5 years.117,122

Dosage in Renal and Hepatic Impairment

Plasma concentrations are higher in individuals with moderate to severe renal impairment compared with individuals with normal renal function.1 The manufacturer makes no specific recommendations for raloxifene dosage adjustment in patients with renal impairment.1

Limited evidence from patients with cirrhosis (Child-Pugh class A) and total serum bilirubin concentrations of 0.6-2 mg/dL indicate that plasma concentrations of raloxifene are 150% higher in such patients relative to plasma concentrations in patients with normal hepatic function.1 Raloxifene has not been evaluated in patients with hepatic impairment other than Child-Pugh class A.1 The manufacturer currently makes no specific recommendation for adjustment of raloxifene dosage in patients with hepatic impairment.1 However, the drug is extensively metabolized in the liver1,27,33,34,35,36,55 and excreted principally in feces.1,45,55,69

Information on the safety of raloxifene has been obtained from phase II and III clinical studies in postmenopausal women who received varying dosages of the drug for the prevention of osteoporosis for 2-30 months.1,2,23,88 Of the more than 2000 women who received raloxifene hydrochloride in these studies, about 40% received 60 mg daily, 40% received 120-600 mg daily, and 20% received 10-50 mg daily.1,2,23 Information has been obtained from clinical studies in women with osteoporosis who received raloxifene hydrochloride 60 or 120 mg daily for 36 months.1,93,98 Information on safety of raloxifene also has been obtained from the Multiple Outcomes of Raloxifene Evaluation (MORE) study, the Continuing Outcomes Relevant to Evista (CORE) study, the Raloxifene Use for the Heart (RUTH) trial, and the Study of Tamoxifen and Raloxifene (STAR) study.1,93,113,114,115,120 Safety of raloxifene in men or in premenopausal women has not been established.1

Raloxifene generally is well tolerated.1,2,23,69,88,93,98,100 The incidence of reported adverse effects in clinical studies generally was similar in patients receiving raloxifene or placebo; however, the incidences of venous thromboembolic events, vasomotor symptoms (i.e., hot flushes [flashes]), and musculoskeletal pain (i.e., leg cramps) were higher in patients receiving raloxifene.1,2,23,69,72,88,93,96,98 In clinical studies that evaluated raloxifene for the prevention or treatment of osteoporosis, about 10.9-11.4% of patients receiving raloxifene hydrochloride discontinued therapy because of adverse effects; this was similar to the 8.8-12.2% discontinuance rate reported with placebo.1 The adverse effect profile suggests that long-term compliance with raloxifene therapy may be more likely than with estrogens.2,5,6,7,16,17,40,41,69,88,91

Cardiovascular Effects

Use of raloxifene did not affect the risk of coronary events in a study in postmenopausal women with coronary heart disease (CHD) or risk factors for CHD (RUTH study).1,115 In the STAR study, the incidence of ischemic heart disease (i.e., myocardial infarction, severe angina, acute ischemic syndrome) in those receiving raloxifene was similar to the incidence in those receiving tamoxifen.113

Limited evidence suggests that women who experienced substantial hypertriglyceridemia (exceeding 5.6 mmol/L or 500 mg/dL) while receiving oral estrogen, alone or in combination with a progestin, may develop increased serum triglyceride concentrations during raloxifene therapy.1

Thromboembolic Events

Raloxifene therapy is associated with an increased risk of venous thromboembolic events such as deep-vein thrombosis and pulmonary embolism.1,55,69,72 The greatest risk for thromboembolic events occurs during the first 4 months of raloxifene therapy.1 In placebo-controlled osteoporosis prevention studies, the risk of deep-vein thrombosis or pulmonary embolism with raloxifene was about 3 times greater than that with placebo,72 a rate that appears similar to that reported in postmenopausal women receiving estrogen replacement therapy.72 Retinal vein occlusion and superficial thrombophlebitis have occurred in women receiving raloxifene.1 Such thromboembolic complications have been associated with raloxifene therapy despite favorable effects on certain clotting factors (e.g., fibrinogen) observed in women receiving the drug, and the relationship, if any, of raloxifene-induced clotting factor changes to thromboembolic phenomena is unclear.91

In the CORE study and the MORE study, the incidence of thromboembolic events was higher in women receiving raloxifene than in those receiving placebo but the differences were not statistically significant.114 Use of raloxifene was associated with an increased risk of venous thromboembolic events in a study that evaluated safety of raloxifene in postmenopausal women with CHD or risk factors for CHD (RUTH study).115 The incidence of total stroke in those receiving raloxifene was similar to the incidence in those receiving placebo in this study; however, use of raloxifene was associated with an increased risk of fatal stroke.1 In the STAR study, the incidence of thromboembolic events (e.g., pulmonary embolism or deep vein thrombosis) was lower with raloxifene compared with tamoxifen.113 The incidence of stroke and transient ischemic attacks was similar for both the raloxifene and tamoxifen groups during the STAR study.113

Vasomotor Symptoms

In clinical studies in postmenopausal women receiving raloxifene for the prevention of osteoporosis, vasomotor symptoms (i.e., hot flushes [flashes]) occurred more frequently in women receiving raloxifene than in those receiving placebo or continuous combined or cyclic estrogen/progestin therapy.1,2,23,69,88 Vasomotor symptoms1,2,23,29,69,88 occurred in 24.6% of patients receiving raloxifene hydrochloride 60 mg daily1,2,88 and required discontinuance of therapy in 1.7% of patients receiving this dosage in clinical trials for the prevention of osteoporosis;1 the incidence of raloxifene-induced vasomotor symptoms appears to be dose related.88 The first episode of vasomotor symptoms generally occurs during the first 6 months of therapy.1 Whether clonidine ameliorates raloxifene-induced hot flushes has not been evaluated.56,91,96 In clinical studies in women with osteoporosis, vasomotor symptoms occurred in about 9.7% of women receiving raloxifene hydrochloride 60 mg daily.1 In the STAR study, women receiving tamoxifen reported more vasomotor symptoms than those receiving raloxifene.120

Other Cardiovascular Effects

Syncope1 or development of a varicose vein condition1 has occurred in up to 2.3% of patients receiving raloxifene in clinical studies.1 In clinical trials, peripheral edema occurred in up to 14.1% of raloxifene-treated women.1

Genitourinary Effects

Breast tenderness/pain1,2,23,88 or vaginal bleeding1,2,88 has been reported in 4.4 or 6.2%, respectively, of postmenopausal women receiving raloxifene in clinical trials for the prevention of osteoporosis.1 Breast pain and vaginal bleeding occur substantially (e.g., 10 times) less frequently in postmenopausal women receiving raloxifene compared with those receiving continuous combined or cyclic estrogen/progestin therapy.23,88 In addition, the incidence of these effects actually appeared to decrease with increasing raloxifene dosage in one study.88 Vaginitis,1,23 urinary tract infection,1 cystitis,1 leukorrhea,1 uterine disorder,1 urinary tract disorder,1 or endometrial disorder1 occurred in up to 4.3, 4, 4.6, 3.3, 3.3, 2.5, or 3.1%, respectively, of postmenopausal women receiving raloxifene in clinical trials.1 In the STAR study, bladder and gynecologic problems, endometrial cancer, and endometrial hyperplasia were reported more frequently in those receiving tamoxifen than in those receiving raloxifene; however, dyspareunia (painful intercourse) was reported more frequently in women receiving raloxifene.120,121

The percentage of sexually active women was lower with raloxifene compared with tamoxifen at nearly every assessment point over the 5-year study duration; among sexually active women, there were increased reports of difficulty with sexual arousal, interest and enjoyment in women receiving raloxifene.120

Clinically and histologically benign endometrial polyps have occurred in women receiving raloxifene.1 In osteoporosis studies in postmenopausal women, there was no evidence of endometrial changes (e.g., hyperplasia) associated with raloxifene therapy.1,88,93

GI Effects

In clinical trials in postmenopausal women receiving raloxifene hydrochloride 60 mg daily, nausea,1,29 diarrhea,1 dyspepsia,1 or vomiting1 occurred in up to 8.8, 7.2, 5.9, or 4.8% of women, respectively.1 Adverse GI effects reported in 2.6-3.3% of patients include flatulence,1 GI disorder,1 and gastroenteritis.1

Musculoskeletal Effects

Musculoskeletal pain (i.e., leg cramps)1,29,55,69,72 has occurred more frequently in postmenopausal women receiving raloxifene compared with placebo.1 In controlled clinical trials, leg cramps/muscle spasms were reported in 7-12% of women receiving raloxifene.1 Arthralgia,1 myalgia,1 arthritis1 , or tendon disorder1 has been reported in up to 15.5, 7.7, 4, or 3.6% of patients receiving raloxifene.1

Sensitivity and Dermatologic Effects

In clinical trials in women receiving raloxifene hydrochloride 60 mg daily, rash1 occurred in 5.5% and sweating1 occurred in 3.1% of patients.

Nervous System Effects

Depression1 or insomnia1 occurred in up to 6.4 or 5.5% of women receiving raloxifene in clinical trials.1 Vertigo,1 neuralgia,1 or hypoesthesia1 have been reported in up to 4.1, 2.4, or 2.1% of women receiving raloxifene.1

Headache or migraine has been reported in 9.2 or 2.4% of women receiving raloxifene hydrochloride 60 mg daily in controlled studies.1

Respiratory Effects

Adverse respiratory effects such as sinusitis,1 rhinitis,1 bronchitis,1 pharyngitis,1 cough,1 pneumonia,1 or laryngitis1 occurred in up to 10.3, 10.2, 9.5, 7.6, 9.3, 2.6, or 2.2%, respectively, of women receiving raloxifene in clinical trials.1

Other Adverse Effects

Infection,1 flu-like syndrome,1 chest pain,1 or fever1 has been reported in up to 15.1, 14.6, 4, or 3.9%, respectively, of women receiving raloxifene in clinical trials.1 Weight gain occurred in 8.8% of raloxifene-treated women.1 Hepatitis has been reported rarely in women receiving raloxifene.97 Platelet counts have been decreased minimally in women receiving raloxifene.1

Use of tamoxifen has been associated with increased rates of cataracts and cataract surgery.113 In the STAR study, fewer cataracts (RR 0.79; 95% confidence interval: 0.68-0.92) and cataract surgeries (RR 0.82; 95% confidence interval: 0.68-0.99) occurred in those receiving raloxifene than in those receiving tamoxifen.113

Precautions and Contraindications

Raloxifene is contraindicated in women with active or past episodes of venous thrombosis, including deep-vein thrombosis, pulmonary embolism, or retinal vein thrombosis.1,52 Potential therapeutic benefit versus risk should be assessed in women at risk of thromboembolic disease secondary to congestive heart failure, superficial thrombophlebitis, or active malignancy.1,2

Patients receiving raloxifene should be informed to notify their clinician if signs or symptoms of a thromboembolic disorder (i.e., thrombophlebitis, pulmonary embolism, retinal thrombosis) occur.52 Because an increased risk of thromboembolic complications associated with prolonged immobilization may occur during raloxifene therapy, the drug should be discontinued at least 72 hours before and withheld during prolonged immobilization (e.g., postsurgery recovery, prolonged bed rest).1,52 Raloxifene therapy may be resumed once the patient is fully ambulatory.1,52 Patients receiving raloxifene should be advised to avoid prolonged restrictions in movement while traveling because of the increased risk of venous thromboembolic events.1,52

Use of raloxifene has been associated with an increased risk of fatal stroke in women with coronary heart disease (CHD) or increased risk for CHD (in the RUTH study).1,115 Therefore, potential therapeutic benefit versus risk should be assessed in women at risk for stroke secondary to a history of stroke or transient ischemic attack [TIA], atrial fibrillation, hypertension, or smoking cigarettes.1

Raloxifene should not be used for the primary or secondary prevention of cardiovascular disease.1 Therapy with raloxifene for 5 years was not associated with cardiovascular benefit in women with CHD or increased risk for CHD (in the RUTH study),1,115

In women with a history of elevated triglyceride concentrations during therapy with oral estrogen (alone or in combination with a progestin), serum triglyceride concentrations should be monitored carefully during raloxifene therapy.1

Postmenopausal women receiving raloxifene for the treatment or prevention of osteoporosis should be advised that the drug should be used in conjunction with other therapeutic measures (diet, adequate vitamin D and calcium intake, weight-bearing exercise) and lifestyle modifications (discontinuance of cigarette smoking, moderation of alcohol consumption).1

Although raloxifene therapy has not been associated with endometrial proliferation, unexplained uterine bleeding should be investigated as clinically indicated.1 Some experts recommend an annual gynecologic examination in women with an intact uterus who are receiving raloxifene for breast cancer risk reduction. 118 While raloxifene therapy has not been associated with breast enlargement, pain, or an increased risk of cancer, any unexplained breast abnormality occurring during raloxifene therapy should be investigated.1 Raloxifene has not been adequately studied to date in women with a history of breast cancer.1

In women experiencing vision problems or who develop cataracts while receiving raloxifene, some experts recommend that an ophthalmology examination be performed. 118

Safety and efficacy of raloxifene have not been evaluated in men.1 Safety of raloxifene in premenopausal women has not been established.1 Because of the potential hazard to the fetus if raloxifene is inadvertently administered during pregnancy, use of the drug in premenopausal women is not recommended by the manufacturer.1

Safety and efficacy of raloxifene have not been established in patients with hepatic impairment, and the drug should be used with caution in such patients.1

Raloxifene should be used with caution in patients with moderate to severe renal impairment.1 Safety and efficacy of the drug have not been established in these patients.1

Because of the embryotoxic and teratogenic effects of the drug, raloxifene is contraindicated in women who are pregnant.1

Pediatric Precautions

The manufacturer states that raloxifene should not be used in pediatric patients.1

Geriatric Precautions

Safety and efficacy of raloxifene in geriatric patients have not been studied specifically to date; however, prevention of osteoporosis, for which safety and efficacy have been established, occurs principally in patients older than 50 years of age.1 When the total number of patients studied in placebo-controlled clinical trials of raloxifene is considered, 61% were 65 years of age or older, while 15.5% were 75 years of age and older.1 No overall differences in efficacy or safety were observed between geriatric and younger patients.1,53,91,96 Pharmacokinetic studies have not revealed age-related differences in pharmacokinetic parameters of the drug in women 42-84 years of age.1 Based on clinical studies with raloxifene, special precautions based on age generally do not appear necessary.91,96

Mutagenicity and Carcinogenicity

The incidence of estrogen-dependent breast cancer or endometrial cancer is being evaluated in completed and ongoing clinical studies that involve over 17,000 women who received at least one dose of raloxifene.1,55,92,93 Analysis at up to 8 years indicates that raloxifene is not associated with an increased risk of endometrial cancer or ovarian cancer compared with placebo.1,55,66,92,93,113,114 Fewer cases of endometrial cancer were reported in women receiving raloxifene compared with tamoxifen in the STAR study; however, the difference between the treatment groups was not statistically significant.113 The annual incidence rates of endometrial cancer (per 1000 women) were 1.25 (raloxifene) and 2 (tamoxifen); the cumulative incidence over 7 years was 8.1 and 14.7 (per 1000 women) for raloxifene and tamoxifen, respectively.113 Although there was no difference in the incidence of endometrial cancer between treatment groups, a statistically significant decrease in uterine hyperplasia with atypia (a risk factor for endometrial cancer) was reported in at-risk women (i.e., those with an intact uterus) receiving raloxifene compared with tamoxifen during the STAR study.113,117

Raloxifene has a protective effect against the development of hormone-sensitive breast cancer.

Raloxifene was not mutagenic in in vitro or in vivo studies, including the Ames microbial test with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the sister chromatid exchange assay in Chinese hamsters, and the micronucleus test in mice.1

In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors (i.e., benign and malignant tumors of granulosa/theca cell origin, benign tumors of epithelial cell origin) in female mice given oral raloxifene hydrochloride 9-242 mg/kg daily (equivalent to systemic exposure of about 0.3-34 times the area under the plasma concentration-time curve [AUC] in women receiving the recommended raloxifene hydrochloride dosage) and an increased incidence of testicular interstitial cell tumors, prostatic adenomas, and adenocarcinomas in male mice given raloxifene hydrochloride 41 or 210 mg/kg daily (4.7 or 24 times the AUC in women).1,96 In a 2-year carcinogenicity study in rats treated during their reproductive lives when ovaries were functional and responsive to hormonal therapy, there was an increased incidence in ovarian tumors (i.e., benign tumors of granulosa/theca cell origin) in female animals given raloxifene hydrochloride 270 mg/kg daily (about 400 times the AUC for women).1,96

Pregnancy, Fertility, and Lactation

Pregnancy

Raloxifene may cause fetal toxicity when administered to pregnant women.1,58,59,60,61,62,63 Effects on reproductive function are expected because raloxifene is an estrogen agonist-antagonist.1,58,59,60,61,62,63 Since the risks clearly outweigh any possible benefits in women who are pregnant, raloxifene is contraindicated in such women; the drug also is not indicated for use in women of childbearing potential.1,57 If raloxifene is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, raloxifene should be discontinued and the patient informed of the potential hazard to the fetus.57,96

In reproductive studies in rabbits using raloxifene hydrochloride doses of 0.1 mg/kg or more (at least 0.04 times the recommended dose in humans on a mg/m² basis), abortion and a low rate of fetal heart anomalies (i.e., ventricular septal defects) were observed, and in rabbits using raloxifene doses of 10 mg/kg or more (at least 4 times the recommended dose in humans on a mg/m² basis), hydrocephaly was observed in the fetuses.1,61 In reproductive studies in rats using raloxifene hydrochloride doses of 1 mg/kg or more (at least 0.2 times the recommended dose in humans on a mg/m² basis), retardation of fetal development and developmental abnormalities (i.e., wavy ribs, kidney cavitation) were observed.1,61

In studies in rats using raloxifene hydrochloride doses of 0.1-10 mg/kg (0.02-1.6 times the recommended dose in humans on a mg/m² basis) during gestation and lactation, 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 were observed.1,60 Disruption of parturition, which resulted in maternal and progeny morbidity and/or death, was observed in rats given raloxifene hydrochloride 10 mg/kg.1,62 While ovarian or vaginal pathology was not observed in adult offspring (4 months of age), uterine hypoplasia and reduced fertility were noted.1,63

Fertility

In male and female rats given raloxifene hydrochloride doses of 5 mg/kg or more (at least 0.8 times the recommended human dose on a mg/m² basis) prior to and during mating, no pregnancies occurred.1 Estrous cycle disruption and inhibition of ovulation were observed in female rats given raloxifene hydrochloride doses of 0.1-10 mg/kg (0.02-1.6 times the recommended human dose on a mg/m² basis); these effects were reversible.1,58 In rats given raloxifene hydrochloride doses of 0.1 mg/kg or more (at least 0.02 times the recommended human dose on a mg/m² basis) during the preimplantation period, delayed and disrupted embryo implantation resulting in prolonged gestation and reduced litter size were observed.1 Changes in sperm production or quality or reproductive performance were not observed in male rats given raloxifene hydrochloride 100 mg/kg daily (16 times the recommended human dosage on a mg/m² basis) for 2 weeks.1,59 The reproductive and developmental effects observed in raloxifene-treated animals are consistent with the estrogen-receptor activity of the drug.1,58,59,60,61,62,63

Lactation

It is not known whether raloxifene distributes into human milk or if the drug affects milk production or the nursing infant;1 however, because raloxifene is an estrogen agonist-antagonist, estrogenic effects on mammary tissue during lactation may be affected.1

Protein-bound Drugs

Raloxifene is more than 95% bound to plasma proteins.1 The manufacturer states that concomitant administration of raloxifene with other highly protein-bound drugs is not expected to affect the plasma concentrations of raloxifene.1 In raloxifene-treated women with osteoporosis, concomitant administration of other highly protein-bound drugs (e.g., gemfibrozil) did not affect the plasma concentrations of raloxifene.1 Raloxifene reportedly does not affect the protein binding of phenytoin, tamoxifen, or warfarin in vitro.1 The manufacturer states that caution is advised if raloxifene is used concomitantly with other highly protein-bound drugs such as diazepam, diazoxide, or lidocaine.1

Estrogens

The manufacturer states that concomitant use of systemic estrogens with raloxifene currently is not recommended because of the lack of experience from prospective clinical trials with such use.1

Antilipemic Agents

Administration of cholestyramine and raloxifene results in a 60% decrease in the absorption and enterohepatic cycling of raloxifene.1,55 The manufacturer states that raloxifene should not be administered with cholestyramine.1,52 Although not studied specifically, other anion-exchange resins would also be expected to decrease the absorption and enterohepatic cycling of raloxifene.1

In raloxifene-treated women with osteoporosis, concomitant administration of gemfibrozil did not affect the plasma concentrations of raloxifene.1

Concomitant use of raloxifene and other antilipemic agents has not been specifically studied.1

Cardiac Glycosides

Raloxifene reportedly does not affect the pharmacokinetics of digoxin.1

Oral Anticoagulants

While the effect of long-term administration of raloxifene in conjunction with warfarin has not been studied and the drug reportedly does not affect the protein binding of the anticoagulant, concomitant administration of single doses of raloxifene and warfarin has resulted in a 10% decrease in prothrombin time compared with administration of warfarin alone.1,55 In raloxifene-treated women with osteoporosis, concomitant administration of warfarin did not affect the plasma concentrations of raloxifene.1 If the drugs are used concomitantly, the patient and prothrombin time should be monitored closely and the dosage of the anticoagulant adjusted accordingly.1,55

Aminopenicillins

Concomitant administration of raloxifene and ampicillin results in a 28% decrease in peak plasma concentration and a 14% decrease in the extent of absorption of raloxifene.1 These changes in raloxifene absorption are consistent with decreased enterohepatic cycling associated with a reduction of enteric bacteria.1 Because systemic exposure and the elimination rate of raloxifene are not affected, raloxifene may be given concomitantly with ampicillin.1

In raloxifene-treated women with osteoporosis, concomitant administration of amoxicillin did not affect the plasma concentrations of raloxifene.1 Raloxifene may be given concomitantly with amoxicillin.1

Antacids

Concomitant administration of raloxifene and calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure to raloxifene.1 Raloxifene may be given concomitantly with antacids.1

Corticosteroids

Pharmacokinetics of methylprednisolone following administration of a single oral dose were not altered in women receiving long-term therapy with raloxifene.1 Raloxifene may be given concomitantly with corticosteroids.1

Other Drugs

Use of raloxifene with cyclosporine has not been evaluated.1

Acute Toxicity

Manifestations

Limited information is available on the acute toxicity of raloxifene.1 Administration of raloxifene hydrochloride 600 mg daily for 8 weeks in a limited number of postmenopausal women was not associated with any unusual adverse effects.1,3

Mortality was not observed in rats or mice following single oral doses of raloxifene hydrochloride 5000 mg/kg (810 or 405 times, respectively, the recommended human dose on a mg/m² basis).1 Mortality was not observed in monkeys following single oral doses of raloxifene hydrochloride 1000 mg/kg (80 times the recommended human dose on a mg/m² basis).1

Treatment

There is no known antidote for raloxifene overdosage.1 If acute overdosage of raloxifene occurs, supportive and symptomatic treatment should be initiated and the patient observed closely.91,96

Pharmacology

Raloxifene is a selective estrogen receptor modulator (SERM) with mixed estrogen agonist or antagonist (antiestrogen) activity in specific tissues.1,2,3,4,5,6,7,8,9,11,12,13,14,15,16,17,18,21,55,64,69,70,88,89,101 Raloxifene exhibits estrogen agonist activity on bone and circulating lipoproteins, but estrogen antagonist activity on breast and uterine tissue.1,2,3,4,5,6,7,8,9,13,14,15,16,17,18,21,28,69,70,88,89,101

Estrogens have an important role in the reproductive, skeletal, cardiovascular, and central nervous systems in women, and act principally by regulating gene expression.1,5,6,7,8,9,11,12,13,14,15,16,17,18,19,20 Biologic response is initiated when estrogen binds to a ligand-binding domain of the estrogen receptor resulting in a conformational change that leads to gene transcription through specific estrogen response elements (ERE) of target gene promoters; subsequent activation or repression of the target gene is mediated through 2 distinct transactivation domains (i.e., AF-1 and AF-2) of the receptor.6,7,8,9,11,12,14,16,19,64 The estrogen receptor also mediates gene transcription using different response elements (i.e., AP-1) and other signal pathways.6,7,8,9,11,12,14,16,19

Recent advances in the molecular pharmacology of estrogen and estrogen receptors have resulted in the development of selective estrogen receptor modulators, agents that bind and activate the estrogen receptor but that exhibit tissue-specific effects distinct from estrogen.1,2,3,5,6,7,8,9,16,17,18,55,64 In addition to raloxifene, agents that have been described as antiestrogens (i.e., clomiphene, tamoxifen, toremifene) are selective estrogen receptor modulators.1,2,3,4,5,6,7,8,9,13,16,17,55,64,91 Although the precise mechanism of action of raloxifene has not been fully elucidated, tissue-specific estrogen-agonist or -antagonist activity of the drug appears to be related to structural differences in the raloxifene-estrogen receptor complex (specifically the surface topography of AF-2) compared with the estrogen (estradiol)-estrogen receptor complex.5,6,7,8,9,10,11,12,13,14,15,16,17,18,37,46,55 A second estrogen receptor also has been identified, and existence of at least 2 estrogen receptors (ERα, ERβ) may contribute to the tissue-specific activity of raloxifene.11,12,16,54 Tissue-selective conversion of metabolite to parent drug does not appear to play a role in the tissue-specific activity of raloxifene.27

Raloxifene has estrogen agonist activity in bone and cardiovascular tissue.1,2,3,4,5,6,7,8,9,16,17,23,26,27,30,46,55,64,69,70 While the role of the estrogen receptor in bone, cardiovascular tissue, and the CNS continues to be studied, emerging evidence indicates that the mechanism of action of estrogen receptors in these tissues differs from the manner in which estrogen receptors function in reproductive tissue.1,5,6,7,8,9,10,11,12,13,14,15,16,17,18,37,46,64,65 In tissues where raloxifene exerts estrogen agonist activity, the raloxifene-estrogen receptor complex binds to DNA sequences distinct from the estrogen receptor element in reproductive tissues.1,5,6,7,8,9,10,11,12,13,14,15,16,17,18,37,46

Effects on Bone

The role of estrogen as a regulator of adult bone mass is well established.1,2,3,4,5,6,7,16,17,19,20,23 The progressive loss of bone mass observed in a large proportion of postmenopausal women is related to decreased ovarian function and to a reduction in the level of circulating estrogens.1,2,3,4,5,6,7,16,17,19,20,23,69 The loss of bone mineral density in these women is largely attributed to bone remodeling imbalances favoring osteoclastic cell-mediated bone resorption; impairment of osteoblasts (or their precursors) and bone formation also may be involved.1,2,3,4,5,6,7,16,17,19,20,23,27 Bone remodeling imbalances resulting from inadequate estrogen concentrations lead to bone formation that is inadequate to offset resorptive losses.1,19,20,40

In postmenopausal women or women who have undergone oophorectomy, the principal pharmacologic action of raloxifene in bone, like that of estrogen replacement therapy, is to decrease the rate of bone resorption, thus slowing the rate of bone loss.1,2,3,4,5,6,7,16,17,19,20,23,37 Estrogens and raloxifene maintain bone mass, in part, through regulation of the gene-encoding transforming growth factor-β3 (TGF-β3).5,6,7,8,9,10,16,17,26,27,54,64 TGF-β3 is a bone matrix protein with antiosteoclastic properties.5,17,26,46,69 In in vitro cell-based assays, raloxifene activates TGF-β3 through pathways that are estrogen receptor-mediated but involve DNA sequences distinct from the estrogen response element.5,6,7,8,9,10,16,17,26,69,91 In addition, raloxifene binds to the estrogen receptor and acts as an estrogen agonist in human preosteoclastic cells resulting in inhibition of their proliferative capacity.26 Inhibition of the proliferative capacity of osteoclastic cells presumably contributes to raloxifene's effects on bone resorption.26 Other mechanisms involved in maintaining bone balance include estrogen-dependent down-regulation of the bone-resorbing cytokine interleukin-6.20,64 Raloxifene, like estrogens, suppresses cytokine interleukin-6 promoter activity.64 Results of in vitro studies indicate that the monoglucuronide conjugates of raloxifene are substantially less effective than raloxifene at inhibiting the resorbing activity of osteoclasts or producing TGF-β3.27

Raloxifene reduces bone resorption and decreases bone turnover as manifested by reductions in serum and urine concentrations of bone turnover markers and increases in bone mineral density (BMD).1,2,5,6,7,8,16,17,23,31,49,69 In osteoporosis treatment and prevention studies, reductions in serum and urine markers of bone turnover (i.e., bone-specific alkaline phosphatase, osteocalcin, collagen breakdown products) generally occurred within 3 months following initiation of raloxifene therapy, peaked within 9-12 months, and persisted throughout the 36- and 24-month observation period.1,2,49,69

The effect of raloxifene versus cyclic estrogen/progestin (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, on days 15-28 of the cycle) on bone remodeling has been evaluated in a limited number of postmenopausal women using radiotracer techniques.1,16,31,69,91 Results of this study suggest that the effects of raloxifene on bone remodeling are similar to those of estrogen/progestin;1,16,31,69,91 at 31 weeks, remodeling suppression was greater with estrogen than raloxifene (i.e., positive shift in calcium balance of 91 versus 60 mg calcium daily, reduction in bone resorption of 162 versus 82 mg calcium daily) but remodeling balance was the same for both agents since bone formation was reduced by estrogen but not by raloxifene.1,31,91 Results from 56 paired bone biopsies obtained at baseline and at year 2 in patients receiving raloxifene for the treatment of osteoporosis indicate that raloxifene therapy is associated with substantial decreases in the bone formation rate per tissue volume; such an effect is consistent with a reduction in bone turnover.1 In addition, normal bone quality was maintained; no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone was observed at year 2 in raloxifene-treated women.1

The skeletal effects of raloxifene have been assessed in several animal models.28,50,69,101 In oophorectomized rats, raloxifene prevented increased bone resorption and bone loss;1,28,46,69,101 raloxifene was associated with positive effects on bone strength, but these effects varied with time.1 In cynomolgus monkeys, administration of raloxifene or conjugated estrogens for 2 years (equivalent to 6 years in humans) suppressed bone turnover and increased the BMD in the lumbar spine and in the central cancellous bone of the proximal tibia.1 In raloxifene- or estrogen-treated cynomolgus monkeys, bone strength (i.e., vertebral compression breaking force) was positively correlated with BMD of the lumbar spine.1 Histologic examination of bone from rats or monkeys given raloxifene did not reveal evidence of woven bone, marrow fibrosis, or mineralization defects.1

The effects of raloxifene on bone in premenopausal women with normal menstrual cycles have not been evaluated.91,96 Although evidence from a pilot trial employing tamoxifen for the prevention of breast cancer suggested that the effects of estrogen agonist-antagonists on bone mineral density (BMD) may depend on menopausal status, with postmenopausal women experiencing positive effects on bone health and premenopausal women experiencing negative effects,90 evidence from animal studies indicates that raloxifene, unlike tamoxifen, does not antagonize the effects of estrogen on bone.30,32 Therefore, raloxifene, unlike tamoxifen, may not decrease BMD in premenopausal women with normal menstrual cycles.30,32,91

Effects on Lipoproteins

Raloxifene, like estrogens, has favorable effects on blood cholesterol.2,3,4,5,6,7,17,23,51,69,70,88,89,115 In a study in postmenopausal women with coronary heart disease or increased risk for coronary heart disease (RUTH study), use of raloxifene was associated with moderate effects on low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol concentrations.115 The magnitude of these effects were of lesser magnitude than changes achieved with other agents known to be cardioprotective.115

Effects on the Uterus and Breast

In contrast to raloxifene's estrogen-agonist effects on bone and on lipoproteins and the cardiovascular system, the drug has estrogen-antagonist activity in the uterus and breast.1,2,3,4,5,6,7,8,9,11,12,13,14,15,16,17,18,28,38,46,69,92,93,101 By comparison, tamoxifen exhibits estrogen antagonist activity in breast tissue but agonist activity in uterine tissue.16,17,55,64

Raloxifene competitively inhibits the binding of estrogen to estrogen receptors in reproductive tissue.7,15,16,17,38,46,64,92 Because raloxifene competes with estrogens for binding to estrogen receptors, raloxifene prevents transcriptional activation of genes containing the estrogen response element.7,15,16,17,38,46,64 While the raloxifene-estrogen receptor complex activates genes through pathways that involve DNA sequences distinct from the estrogen response element in bone tissues, the raloxifene-estrogen receptor complex does not appear to have intrinsic activity in transcriptional activation of genes in reproductive tissues.46 Direct inhibition of estrogen binding to its receptor contributes to the estrogen-antagonist activity of raloxifene,7,15,16,17,38,46,64 but other mechanisms also are involved.12,16,25,38,64

Raloxifene does not exhibit uterotropic activity.2,3,4,5,6,7,8,9,11,18,28,55 Studies in rats indicate that raloxifene, in contrast to estrogens and tamoxifen, produces marginal increases in uterine weight without endometrial proliferation.18,28,46,69 While estrogens (e.g., estradiol) and tamoxifen presumably mediate uterine activity through an AP-1 response element, raloxifene is not active at this site, and lack of affinity for the AP-1 site in uterine tissue may account for raloxifene's lack of uterine stimulatory activity.8,12,91,96

In postmenopausal women, raloxifene does not appear to stimulate endometrial development and may inhibit endometrial proliferation that occurs in the presence of low concentrations of endogenous estrogen.2,3,18,23,69,93 Endometrial thickness has been evaluated in women enrolled in the osteoporosis treatment and prevention studies.1,93 In the osteoporosis treatment study, evaluation at 36 months indicated that raloxifene-treated women had a mean 0.06-mm increase in endometrial thickness over baseline and placebo-treated women had a mean 0.27-mm decrease.1 In the osteoporosis prevention study, endometrial thickness measurements in postmenopausal women receiving raloxifene were similar to measurements reported in women receiving placebo; evaluation at 24 months (using transvaginal ultrasonography) indicated that raloxifene-treated women had a mean 0.09-mm increase in endometrial thickness over baseline and placebo-treated women had a mean 0.04-mm increase.1 During the STAR study, women receiving both raloxifene and tamoxifen were required to undergo an annual gynecologic examination.113 Endometrial or uterine hyperplasia (with or without atypia) was reported in a small number of women receiving raloxifene as chemoprevention for breast cancer in this study; the number of cases of endometrial hyperplasia was considerably lower with raloxifene compared with tamoxifen (14 versus 84 cases). 113

The endometrial effect of raloxifene in premenopausal women with normal concentrations of endogenous estrogens differs from the effect in postmenopausal women.17,18 In a limited number of premenopausal women with normal menstrual cycles receiving raloxifene hydrochloride 100 or 200 mg daily for 28 days, subtle morphologic changes that could result from estrogen antagonist activity of the drug were noted in follicular and luteal phase biopsies; however, definite antagonist activity was not established.18

Raloxifene inhibits estradiol-dependent proliferation of MCF-7 human mammary tumor cells in vitro.7,16,17,43,69 On a molar basis, raloxifene is about 60-1000 times more potent than tamoxifen as an inhibitor of estrogen-stimulated proliferation of the MCF-7 human mammary tumor cell line;27,43,73,74 however, potency of the 4-hydroxy metabolite of tamoxifen in inhibiting such proliferation is comparable to that of raloxifene.43 In vitro, raloxifene also has been shown to inhibit the invasiveness of these cells, whereas tamoxifen enhanced their invasiveness.43,76 In MCF-7 breast cancer cell-related assays, the monoglucuronide conjugates of raloxifene are substantially less potent than raloxifene at inhibiting cell proliferation.27 While raloxifene has antitumor activity in vivo, tamoxifen produced greater levels of efficacy against mammary tumors in most in vivo tumor prevention studies.7,16,17,43,77 The pharmacologic disparity between in vitro and in vivo results for tamoxifen and raloxifene has been attributed to activity of tamoxifen's 4-hydroxy metabolite in vivo.43 Raloxifene does not exhibit antiproliferative effects on nonestrogen-dependent (i.e., androgen-sensitive) mammary tumor cell lines.43,69,75

Other Effects

The activity of raloxifene on estrogen receptors in the CNS remains to be determined; however, the drug does not appear to ameliorate the vasomotor or psychologic manifestations associated with estrogen deficiency.5,6

Pharmacokinetics

The pharmacokinetics of raloxifene have been studied principally in postmenopausal women.1,33,35,69 Pharmacokinetic parameters of raloxifene show considerable interindividual variation; however, studies in a limited number of individuals have not revealed gender- or race-related differences.1,33,69 In addition, there has been no evidence of age-related differences in the pharmacokinetics of the drug in women 42-84 years of a the pharmacokinetics in children have not been determined.1 Limited information is available on the pharmacokinetics of raloxifene in individuals with hepatic and/or renal impairment.1

Absorption

Raloxifene is rapidly absorbed from the GI tract.1,27,33,34,35,45,69 Because raloxifene undergoes extensive first-pass glucuronidation, oral bioavailability of unchanged drug is low.1,27,33,34,35,45 While approximately 60% of an oral dose is absorbed, absolute bioavailability as unchanged raloxifene is only 2%.1,55 However, systemic availability of raloxifene may be greater than that indicated in bioavailability studies because circulating glucuronide conjugates are converted back to parent drug in various tissues.1,27

Raloxifene undergoes extensive first-pass glucuronidation and enterohepatic circulation, and peak plasma concentrations of the glucuronide conjugates of raloxifene are achieved more rapidly than peak plasma concentrations of the parent drug.1,30,33,35,91,96 Following oral administration of a single 120- or 150-mg dose of raloxifene hydrochloride, peak plasma concentrations of raloxifene and its glucuronide conjugates are achieved at 6 and 1 hour, respectively.33,35 Plasma concentrations of raloxifene's glucuronide conjugates exceed those of the parent drug,1,33,35,45 and the time to achieve maximum concentrations of the drug and glucuronide metabolites depends on the extent and rate of systemic interconversion and enterohepatic circulation.1,27 Following oral administration of radiolabeled raloxifene, less than 1% of total circulating radiolabeled material in plasma represented parent drug.1,45

Using data normalized for a single 60-mg dose and a 60-kg body weight, oral administration of raloxifene hydrochloride in postmenopausal women would be expected to result in mean peak plasma raloxifene concentrations of 0.5 ng/mL and oral administration of multiple 60-mg doses in mean peak plasma raloxifene concentrations of 1.36 ng/mL.1,96 Area under the plasma concentration-time curve (AUC) of raloxifene following a single dose is essentially the same as the AUC following multiple doses of the drug.1 Increasing the dose of raloxifene hydrochloride over a range of 30-150 mg results in a slightly less than proportional increase in the AUC of raloxifene.1 Administration of raloxifene with a standardized high-fat meal increases the peak plasma concentration and AUC of raloxifene 28 and 16%, respectively, compared with administration on an empty stomach but does not result in clinically important changes in systemic exposure.1

Results of a single-dose study in patients with cirrhosis of the liver (Child-Pugh class A) and total serum bilirubin concentrations of 0.6-2 mg/dL indicate that plasma raloxifene concentrations correlate with serum bilirubin concentrations and are 150% higher in such individuals compared with individuals with normal hepatic function.1

In postmenopausal women receiving raloxifene in clinical trials, plasma concentrations of raloxifene in those with mild renal impairment were similar to values in women with normal renal function.1,96 Results of a single-dose study in individuals with moderate renal impairment (creatinine clearance of 31-50 mL/minute) or severe renal impairment (creatinine clearance of 30 mL/minute or less) indicate that plasma raloxifene concentrations (area under the plasma concentration-time curve) are 122% higher in such individuals compared with individuals with normal renal function.1

Distribution

Distribution of raloxifene into body tissues and fluids has not been fully characterized.1,91 Raloxifene and raloxifene 4'-glucuronide have been detected in saliva following oral administration of radiolabeled drug.45 In studies in rats given radiolabeled raloxifene 6-glucuronide, the liver contained the highest concentration of radioactivity, followed by serum, lung, and kidney.27 While bone and the uterus contained relatively low concentrations of radiolabeled metabolite, 24% of the radioactivity in bone, 14% in the uterus, and 23% in the liver represented raloxifene.27 Results of this study indicate that the conversion of metabolite to parent drug occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone, and uterus.27

The apparent volume of distribution following oral administration of single doses of raloxifene hydrochloride 30-150 mg is 2348 L/kg, suggesting extensive tissue distribution.1 The volume of distribution reportedly is not dose dependent over a dosage range of 30-150 mg daily.1

Raloxifene and its monoglucuronide conjugates are more than 95% bound to plasma proteins.1,69,96 Raloxifene binds to albumin and α₁-acid glycoprotein (α₁-AGP), but not to testosterone-estradiol binding globulin (sex hormone binding globulin).1

It is not known if raloxifene is distributed into milk.1

Elimination

Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates raloxifene 4'-glucuronide, 6-glucuronide, and 6,4'-diglucuronide.1,27,33,34,35,36,55 Metabolism of raloxifene does not appear to be mediated by cytochrome P-450 enzymes, since metabolites other than glucuronide conjugates have not been identified.1

The plasma elimination half-life of raloxifene at steady-state averages 32.5 hours (range: 15.8-86.6 hours).1,55 The terminal log-linear portions of the plasma clearance curves for raloxifene and its glucuronide conjugates generally are parallel.1,33 Following IV administration, raloxifene is cleared from systemic circulation at a rate approximating hepatic blood flow.1 Following oral administration of a single dose, apparent oral clearance of the drug is 44.1 L/hour per kg.1,96

Raloxifene is excreted principally in feces as unabsorbed drug and via biliary elimination as glucuronide conjugates, which subsequently are metabolized by bacteria in the GI tract to the parent drug.1,45,55,69,96 Following oral administration, less than 6 or 0.2% of a raloxifene dose is excreted as glucuronide conjugates or parent drug, respectively, in urine.1,45,69

Chemistry and Stability

Chemistry

Raloxifene hydrochloride, a nonsteroidal benzothiophene derivative, is an estrogen agonist-antagonist.1,2,3,13,14,15,16,17,55,69,70 The drug also has been referred to as a selective estrogen receptor modulator (SERM).1,2,3,13,14,15,16,17,55,69,70,101 Raloxifene differs chemically and pharmacologically from naturally occurring estrogens, synthetic steroidal and nonsteroidal compounds with estrogenic activity, and agents that have been described as antiestrogens (e.g., clomiphene, tamoxifen, toremifene).4,13,14,15,16,17 However, like clomiphene, tamoxifen, and toremifene, raloxifene exhibits both estrogen agonist and antagonist (antiestrogen) activity, although the overall pharmacologic profiles of the drugs differ.1,2,3,16,17,64,101 Differences in the pharmacologic activity of raloxifene versus estradiol, tamoxifen, or toremifene are thought to depend on the 3-dimensional configuration of each drug.5,6,7,8,9,10,11,12,13,14,15,16,17,18,37,46,55,64

Raloxifene consists of a 2-arylbenzothiophene core and a piperidine-containing basic side chain.1,13,14,15,16,17 Presence of hydroxy groups at positions 6 and 4' of the 2-arylbenzothiophene core are important for estrogen receptor binding and correspond to the 3- and 17β-hydroxy substituents of estradiol.13,14,101 While raloxifene binds at the same site as estradiol within the ligand-binding domain of the estrogen receptor, the binding mode of the 4' hydroxyl group and presence of the piperidine-containing basic side chain of raloxifene results in a drug-estrogen receptor complex that differs structurally and biologically from the estradiol-estrogen receptor complex.5,6,7,8,9,10,11,12,13,14,15,16,17,18,37,46,55 The orientation of the basic side chain is important in determining the uterine activity profile of selective estrogen-receptor modulators; the planar orientation and presence of the piperidine ring on the basic side chain of raloxifene result in a compound that lacks uterine estrogen agonist activity.15,17,101

Raloxifene hydrochloride occurs as an off-white to pale yellow or greenish-yellow powder.1,67 The drug has solubilities of 0.3 mg/mL in water at 25°C and 1.6 mg/mL in alcohol at 25°C.67

Stability

Commercially available raloxifene hydrochloride tablets should be stored at controlled room temperature (20-25°C).1 When stored as directed, the tablets have an expiration date of 2 years following the date of manufacture.67

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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