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raloxifene hcl 60 mg tablet generic evista

Out of Stock Manufacturer AMNEAL PHARMACE 65162005710
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Uses

Osteoporosis

Raloxifene is used for the prevention and treatment of osteoporosis in postmenopausal women. Safety and efficacy in premenopausal women have not been established.

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. 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. 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. Risk factors include premature ovarian failure; a family history of osteoporosis; a small, slim body frame; endocrine disorders such as thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, and insulin-dependent diabetes mellitus (type 1, IDDM); cigarette smoking; drinking excessive amounts of alcohol; a sedentary life-style and/or lack of physical exercise; low body weight; and low dietary calcium intake. White or Asian women, particularly those who are thin or small and have a positive family history of osteoporosis, are at a higher risk for the disease than are black women. Increased bone turnover as manifested by increased serum and urine markers of bone turnover and low bone mineral density (BMD) (e.g., at least 1 standard deviation below the premenopausal mean) as determined by densitometric techniques also are risk factors. Premature ovarian failure (surgical or nonsurgical) hastens the onset of osteoporosis, and estrogen deficiency in premenopausal women (e.g., secondary to anorexia nervosa- or exercise-induced amenorrhea, or to hyperprolactinemia) induces bone loss and may reduce peak bone mass.

Osteoporosis may be confirmed by the finding of a low bone mass (e.g., at least 2 or 2.5 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture.

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. The goal of preventive therapy is preservation of bone mass and a resultant decrease in fracture risk. Unlike estrogens, raloxifene is not effective in relieving vasomotor symptoms (hot flushes [ flashes]) associated with estrogen deficiency.(See Cautions: Cardiovascular Effects.) The efficacy of raloxifene in preventing other forms of osteoporosis (e.g., drug [ such as corticosteroid]-induced) remains to be established.

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). All women received 400-600 mg of elemental calcium daily in addition to their usual dietary calcium intake. 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. 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. Increases in total body BMD of 1.3-2% compared with placebo (i.e., calcium) have been reported in raloxifene-treated women. 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. 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. The effect of raloxifene therapy for longer than 2 years is being investigated in ongoing studies. Whether increases in BMD are maintained following withdrawal of raloxifene has not been established. The effect of raloxifene therapy on forearm BMD remains to be determined. 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).

The effect of raloxifene on BMD versus estrogens or alendronate has been evaluated in several clinical studies. 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. 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. 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. 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. 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%.

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). 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. 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. 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. However, clinical experience with raloxifene is limited compared with estrogen replacement therapy, and the effect of raloxifene on fracture rates has not been established. The role of raloxifene versus alendronate also has not been established. 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.

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. Although raloxifene preventive therapy was initiated at a median of 5 years postmenopause in clinical trials, 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. If preventive therapy is not initiated soon after menopause, some benefit also may be likely with delayed initiation. In general, exercise and adequate calcium and vitamin D intake should be encouraged for all women. 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.

Treatment in Postmenopausal Women

Raloxifene is used for the treatment of osteoporosis in postmenopausal women. Estrogen replacement therapy is effective for the treatment of osteoporosis in postmenopausal women and has been recommended as first-line therapy for women with osteoporosis. However, because results of a recent controlled study indicate that estrogen/progestin therapy is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism, recommendations on the appropriate use of such therapy are being revised. Other therapeutic modalities for the treatment of osteoporosis include alendronate, calcitonin, calcium, risedronate, and vitamin D.Therapy with alendronate reduces spine and nonspine fracture rates in women with osteoporosis. While recent evidence indicates that raloxifene reduces the risk of vertebral fracture in women with osteoporosis, 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. The role of raloxifene in the treatment of osteoporosis may be determined by the effect of the drug on breast cancer.(See Breast Cancer: Reduction in the Incidence of Breast Cancer in Women with Osteoporosis, in Uses.)

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). 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. 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).

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. 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. In this study, women receiving raloxifene had fewer new vertebral fractures regardless of vertebral fracture status at the beginning of the study. 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%). 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%). In women with one or more baseline fractures, the incidence of new fractures was 10.7% in women receiving raloxifene hydrochloride 120 mg daily. Fewer raloxifene-treated women (1.8%) experienced one or more new symptomatic vertebral fractures than placebo-treated women (3.1%). 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. A reduction in nonspinal fractures was not observed in raloxifene-treated women at month 36.

Use in Premenopausal Women

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

Corticosteroid-induced Hypogonadism and Osteoporosis

Patients receiving long-term corticosteroid therapy may develop hypogonadism secondary to inhibition of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary as well as secondary to direct effects on the ovaries and testes, and such hypogonadism may be associated with bone loss. Therefore, all patients receiving prolonged corticosteroid therapy should be assessed for possible hypogonadism, which should be corrected if present. Hormone replacement therapy (HRT, combined estrogen and progestin therapy) has been effective in increasing bone mass density (BMD) in postmenopausal women with asthma or rheumatoid arthritis who were receiving chronic corticosteroid therapy. Although the efficacy of raloxifene for the prevention or treatment of corticosteroid-induced bone loss remains to be established, some experts (e.g., the American College of Rheumatology) currently state that raloxifene theoretically should be effective in preventing such bone loss and therefore can be offered to selected postmenopausal corticosteroid-treated women who refuse HRT therapy or other antiresorptive agents (e.g., bisphosphonates, calcitonin) or in whom such therapies are contraindicated.

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. Raloxifene should not be used to reduce the risk of breast cancer in premenopausal women.

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

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. 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. 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. 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. During the 8 years of the MORE and CORE study, the incidence of invasive breast cancer and ER-positive positive breast cancer was reduced by 66 and 76%, respectively, in those receiving raloxifene compared with those receiving placebo. The incidence of noninvasive breast cancer in women receiving raloxifene was similar to that in women receiving placebo.

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.

Experts consider use of raloxifene an option in postmenopausal women 35 years of age or older who are considered 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. 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.

The effects of raloxifene versus tamoxifen on reducing the incidence of breast cancer was evaluated in a clinical trial known as STAR (Study of Tamoxifen and Raloxifene). This study enrolled postmenopausal women at least 35 years of age who were at high risk for developing breast cancer. Breast cancer risk was determined using the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool based on a statistical model (the Gail model). 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. 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. 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. Results from the STAR study showed that raloxifene and tamoxifen were equivalent in efficacy in lowering the risk of invasive breast cancer (4.3 per 1000 in the tamoxifen group versus 4.41 per 1000 in the raloxifene group). 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); the clinical importance of this finding remains to be determined. Use of raloxifene was associated with a lower risk of thromboembolic events than use of tamoxifen; there was no difference in the rates of myocardial infarction, severe angina, or acute ischemic syndrome between the tamoxifen and raloxifene groups. Rates of fracture were essentially identical in the raloxifene and tamoxifen groups. There were fewer cataracts in the raloxifene group than in the tamoxifen group.

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. 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. Fewer cases of endometrial cancer were reported in women receiving raloxifene compared with tamoxifen, but the difference was not statistically significant.(See Cautions: Genitourinary Effects.)

The effect of raloxifene on the reduction in breast cancer incidence in women with BRCA1 or BRCA2 genetic mutations has not been established. 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.

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). 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. 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. (See Cautions: Cardiovascular Effects and Cautions: Precautions and Contraindications.)

Dosage and Administration

Administration

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

Dosage

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

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

Osteoporosis

Prevention in Postmenopausal Women

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

Treatment in Postmenopausal Women

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

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. The American Society of Clinical Oncology (ASCO) recommends a treatment duration of 5 years. 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.

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. The manufacturer makes no specific recommendations for raloxifene dosage adjustment in patients with renal impairment.

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. Raloxifene has not been evaluated in patients with hepatic impairment other than Child-Pugh class A. The manufacturer currently makes no specific recommendation for adjustment of raloxifene dosage in patients with hepatic impairment. However, the drug is extensively metabolized in the liver and excreted principally in feces.

Cautions

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. 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. Information has been obtained from clinical studies in women with osteoporosis who received raloxifene hydrochloride 60 or 120 mg daily for 36 months. 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. Safety of raloxifene in men or in premenopausal women has not been established.

Raloxifene generally is well tolerated. 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. 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. The adverse effect profile suggests that long-term compliance with raloxifene therapy may be more likely than with estrogens.

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). 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.

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.

Thromboembolic Events

Raloxifene therapy is associated with an increased risk of venous thromboembolic events such as deep-vein thrombosis and pulmonary embolism. The greatest risk for thromboembolic events occurs during the first 4 months of raloxifene therapy. 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, a rate that appears similar to that reported in postmenopausal women receiving estrogen replacement therapy. Retinal vein occlusion and superficial thrombophlebitis have occurred in women receiving raloxifene. 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.

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. 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). 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. In the STAR study, the incidence of thromboembolic events (e.g., pulmonary embolism or deep vein thrombosis) was lower with raloxifene compared with tamoxifen. The incidence of stroke and transient ischemic attacks was similar for both the raloxifene and tamoxifen groups during the STAR study.

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. Vasomotor symptoms occurred in 24.6% of patients receiving raloxifene hydrochloride 60 mg daily and required discontinuance of therapy in 1.7% of patients receiving this dosage in clinical trials for the prevention of osteoporosis; the incidence of raloxifene-induced vasomotor symptoms appears to be dose related. The first episode of vasomotor symptoms generally occurs during the first 6 months of therapy. Whether clonidine ameliorates raloxifene-induced hot flushes has not been evaluated. In clinical studies in women with osteoporosis, vasomotor symptoms occurred in about 9.7% of women receiving raloxifene hydrochloride 60 mg daily. In the STAR study, women receiving tamoxifen reported more vasomotor symptoms than those receiving raloxifene.

Other Cardiovascular Effects

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

Genitourinary Effects

Breast tenderness/pain or vaginal bleeding has been reported in 4.4 or 6.2%, respectively, of postmenopausal women receiving raloxifene in clinical trials for the prevention of osteoporosis. 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. In addition, the incidence of these effects actually appeared to decrease with increasing raloxifene dosage in one study. Vaginitis, urinary tract infection, cystitis, leukorrhea, uterine disorder, urinary tract disorder, or endometrial disorder 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. In the STAR study, bladder and gynecologic problems 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.

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.

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

GI Effects

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

Musculoskeletal Effects

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

Sensitivity and Dermatologic Effects

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

Nervous System Effects

Depression or insomnia occurred in up to 6.4 or 5.5% of women receiving raloxifene in clinical trials. Vertigo, neuralgia, or hypoesthesia have been reported in up to 4.1, 2.4, or 2.1% of women receiving raloxifene.

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

Respiratory Effects

Adverse respiratory effects such as sinusitis, rhinitis, bronchitis, pharyngitis, cough, pneumonia, or laryngitis 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.

Other Adverse Effects

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

Use of tamoxifen has been associated with increased rates of cataracts and cataract surgery. 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.

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. 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.

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. 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). Raloxifene therapy may be resumed once the patient is fully ambulatory. Patients receiving raloxifene should be advised to avoid prolonged restrictions in movement while traveling because of the increased risk of venous thromboembolic events.

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). 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.

Raloxifene should not be used for the primary or secondary prevention of cardiovascular disease. 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),

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.

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).

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

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

Safety and efficacy of raloxifene have not been evaluated in men. Safety of raloxifene in premenopausal women has not been established and use of the drug in such women currently is not recommended by the manufacturer.

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.

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

Because of the embryotoxic and teratogenic effects of the drug, raloxifene should not be initiated in women who are or may become pregnant. Raloxifene is contraindicated in lactating women.(See Cautions: Pregnancy, Fertility, and Lactation.)

Pediatric Precautions

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

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. 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. No overall differences in efficacy or safety were observed between geriatric and younger patients. Pharmacokinetic studies have not revealed age-related differences in pharmacokinetic parameters of the drug in women 42-84 years of age. Based on clinical studies with raloxifene, special precautions based on age generally do not appear necessary.

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. 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. 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. 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. 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.

Raloxifene has a protective effect against the development of hormone-sensitive breast cancer. (See Uses: 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.

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). 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).

Pregnancy, Fertility, and Lactation

Pregnancy

Raloxifene may cause fetal toxicity when administered to pregnant women. Effects on reproductive function are expected because raloxifene is an estrogen agonist-antagonist. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, raloxifene is contraindicated in such women. 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.

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/m 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/m basis), hydrocephaly was observed in the fetuses. 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/m basis), retardation of fetal development and developmental abnormalities (i.e., wavy ribs, kidney cavitation) were observed.

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/m 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. Disruption of parturition, which resulted in maternal and progeny morbidity and/or death, was observed in rats given raloxifene hydrochloride 10 mg/kg. While ovarian or vaginal pathology was not observed in adult offspring (4 months of age), uterine hypoplasia and reduced fertility were noted.

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/m basis) prior to and during mating, no pregnancies occurred. 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/m basis); these effects were reversible. 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/m basis) during the preimplantation period, delayed and disrupted embryo implantation resulting in prolonged gestation and reduced litter size were observed. 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/m basis) for 2 weeks. The reproductive and developmental effects observed in raloxifene-treated animals are consistent with the estrogen-receptor activity of the drug.

Lactation

Raloxifene is contraindicated in lactating women. It is not known if raloxifene is distributed into human milk.

Drug Interactions

Protein-bound Drugs

Raloxifene is more than 95% bound to plasma proteins. The manufacturer states that concomitant administration of raloxifene with other highly protein-bound drugs is not expected to affect the plasma concentrations of raloxifene. 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. Raloxifene reportedly does not affect the protein binding of phenytoin, tamoxifen, or warfarin (see Drug Interactions: Oral Anticoagulants) in vitro. The manufacturer states that caution is advised if raloxifene is used concomitantly with other highly protein-bound drugs such as diazepam, diazoxide, or lidocaine.

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.

Antilipemic Agents

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

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

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

Cardiac Glycosides

Raloxifene reportedly does not affect the pharmacokinetics of digoxin.

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. In raloxifene-treated women with osteoporosis, concomitant administration of warfarin did not affect the plasma concentrations of raloxifene. If the drugs are used concomitantly, the patient and prothrombin time should be monitored closely and the dosage of the anticoagulant adjusted accordingly.

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. These changes in raloxifene absorption are consistent with decreased enterohepatic cycling associated with a reduction of enteric bacteria. Because systemic exposure and the elimination rate of raloxifene are not affected, raloxifene may be given concomitantly with ampicillin.

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

Antacids

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

Corticosteroids

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

Other Drugs

Use of raloxifene with cyclosporine has not been evaluated.

Pharmacokinetics

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

Absorption

Raloxifene is rapidly absorbed from the GI tract. Because raloxifene undergoes extensive first-pass glucuronidation, oral bioavailability of unchanged drug is low. While approximately 60% of an oral dose is absorbed, absolute bioavailability as unchanged raloxifene is only 2%. 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.

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. 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. Plasma concentrations of raloxifene's glucuronide conjugates exceed those of the parent drug, 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. Following oral administration of radiolabeled raloxifene, less than 1% of total circulating radiolabeled material in plasma represented parent drug.

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. 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. 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. 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.

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.

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.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.

Distribution

Distribution of raloxifene into body tissues and fluids has not been fully characterized. Raloxifene and raloxifene 4'-glucuronide have been detected in saliva following oral administration of radiolabeled drug. In studies in rats given radiolabeled raloxifene 6-glucuronide, the liver contained the highest concentration of radioactivity, followed by serum, lung, and kidney. 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. 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.

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. The volume of distribution reportedly is not dose dependent over a dosage range of 30-150 mg daily.

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

It is not known if raloxifene is distributed into milk.

Elimination

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

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

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. Following oral administration, less than 6 or 0.2% of a raloxifene dose is excreted as glucuronide conjugates or parent drug, respectively, in urine.

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