Raloxifene Drug Information
Generic name: RALOXIFENE HYDROCHLORIDE
Uses of Raloxifene
Treatment and Prevention of Osteoporosis in Postmenopausal Women Raloxifene hydrochloride tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women.
Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis.
Dosage & Administration of Raloxifene
Recommended Dosing
The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals. For the indications in risk of invasive breast cancer the optimum duration of treatment is not known.
Recommendations for Calcium and Vitamin D Supplementation
For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones.
The recommended intake of vitamin D is 400 to 800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered.
Side Effects of Raloxifene
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Osteoporosis Treatment Clinical Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride-treated women and 8.8% of placebo-treated women.
Venous Thromboembolism: The most serious adverse reaction related to raloxifene hydrochloride was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with raloxifene hydrochloride. Common adverse reactions considered to be related to raloxifene hydrochloride therapy were hot flashes and leg cramps.
Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on raloxifene hydrochloride. Placebo-Controlled Osteoporosis Prevention Clinical Trials — The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups.
Discontinuation rates due to hot flashes did not differ significantly between raloxifene hydrochloride and placebo groups (1.7% and 2.2%, respectively). Hot flashes occurred in about one in four patients on raloxifene hydrochloride versus about one in six on placebo. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment.
Table 1 lists adverse reactions occurring in either the osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency ≥2% in either group and in more raloxifene hydrochloride-treated women than in placebo-treated women. Adverse reactions are shown without attribution of causality. The majority of adverse reactions occurring during the studies were mild and generally did not require discontinuation of therapy.
Table 1: Adverse Reactions Occurring in Placebo-Controlled Osteoporosis Clinical Trials at a Frequency ≥ 2% and in More Raloxifene Hydrochloride-Treated (60 mg Once Daily) Women than Placebo-Treated Women a A A Comparison of Raloxifene Hydrochloride and Hormone Therapy — Raloxifene hydrochloride was compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis. Table 2 shows adverse reactions occurring more frequently in one treatment group and at an incidence ≥2% in any group. Table 2: Adverse Reactions Reported in the Clinical Trials for Osteoporosis Prevention with Raloxifene Hydrochloride (60 mg Once Daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (Hormone Therapy) at an Incidence ≥2% in any — Across all placebo-controlled trials, raloxifene hydrochloride was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness.
Raloxifene hydrochloride was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin. Gynecologic Cancers — Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer. Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH) — The safety of raloxifene hydrochloride (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55 to 92) with documented coronary heart disease (CHD) or multiple CHD risk factors.
Median study drug exposure was 5.1 years for both treatment groups. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups. As of 31 December 2005, the median follow-up was 4.3 years.
The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials.
Postmarketing Experience
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported very rarely since market introduction include retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE).
| Treatment | Prevention | |||
|---|---|---|---|---|
| Raloxifene Hydrochloride (N=2557) % | Placebo (N=2576) % | Raloxifene Hydrochloride (N=581) % | Placebo (N=584) % | |
| a A: Placebo incidence greater than or equal to raloxifene hydrochloride incidence; B: Less than 2% incidence and more frequent with raloxifene hydrochloride. b Includes only patients with an intact uterus: Prevention Trials: raloxifene hydrochloride, n=354, Placebo, n=364; Treatment Trial: raloxifene hydrochloride, n=1948, Placebo, n=1999. c Actual terms most frequently referred to endometrial fluid. | ||||
| Body as a Whole | ||||
| Infection | A | A | 15.1 | 14.6 |
| Flu Syndrome | 13.5 | 11.4 | 14.6 | 13.5 |
| Headache | 9.2 | 8.5 | A | A |
| Leg Cramps | 7 | 3.7 | 5.9 | 1.9 |
| Chest Pain | A | A | 4 | 3.6 |
| Fever | 3.9 | 3.8 | 3.1 | 2.6 |
| Cardiovascular System | ||||
| Hot Flashes | 9.7 | 6.4 | 24.6 | 18.3 |
| Migraine | A | A | 2.4 | 2.1 |
| Syncope | 2.3 | 2.1 | B | B |
| Varicose Vein | 2.2 | 1.5 | A | A |
| Digestive System | ||||
| Nausea | 8.3 | 7.8 | 8.8 | 8.6 |
| Diarrhea | 7.2 | 6.9 | A | A |
| Dyspepsia | A | A | 5.9 | 5.8 |
| Vomiting | 4.8 | 4.3 | 3.4 | 3.3 |
| Flatulence | A | A | 3.1 | 2.4 |
| Gastrointestinal Disorder | A | A | 3.3 | 2.1 |
| Gastroenteritis | B | B | 2.6 | 2.1 |
| Metabolic and Nutritional | ||||
| Weight Gain | A | A | 8.8 | 6.8 |
| Peripheral Edema | 5.2 | 4.4 | 3.3 | 1.9 |
| Musculoskeletal System | ||||
| Arthralgia | 15.5 | 14 | 10.7 | 10.1 |
| Myalgia | A | A | 7.7 | 6.2 |
| Arthritis | A | A | 4 | 3.6 |
| Tendon Disorder | 3.6 | 3.1 | A | A |
| Nervous System | ||||
| Depression | A | A | 6.4 | 6 |
| Insomnia | A | A | 5.5 | 4.3 |
| Vertigo | 4.1 | 3.7 | A | A |
| Neuralgia | 2.4 | 1.9 | B | B |
| Hypesthesia | 2.1 | 2 | B | B |
| Respiratory System | ||||
| Sinusitis | 7.9 | 7.5 | 10.3 | 6.5 |
| Rhinitis | 10.2 | 10.1 | A | A |
| Bronchitis | 9.5 | 8.6 | A | A |
| Pharyngitis | 5.3 | 5.1 | 7.6 | 7.2 |
| Cough Increased | 9.3 | 9.2 | 6 | 5.7 |
| Pneumonia | A | A | 2.6 | 1.5 |
| Laryngitis | B | B | 2.2 | 1.4 |
| Skin and Appendages | ||||
| Rash | A | A | 5.5 | 3.8 |
| Sweating | 2.5 | 2 | 3.1 | 1.7 |
| Special Senses | ||||
| Conjunctivitis | 2.2 | 1.7 | A | A |
| Urogenital System | ||||
| Vaginitis | A | A | 4.3 | 3.6 |
| Urinary Tract Infection | A | A | 4 | 3.9 |
| Cystitis | 4.6 | 4.5 | 3.3 | 3.1 |
| Leukorrhea | A | A | 3.3 | 1.7 |
| Uterine Disorder b, c | 3.3 | 2.3 | A | A |
| Endometrial Disorder b | B | B | 3.1 | 1.9 |
| Vaginal Hemorrhage | 2.5 | 2.4 | A | A |
| Urinary Tract Disorder | 2.5 | 2.1 | A | A |
| Raloxifene Hydrochloride (N=317) % | Hormone Therapy- Continuous Combined b (N=96) % | Hormone Therapy-Cyclic c (N=219) % | |
|---|---|---|---|
| a These data are from both blinded and open-label studies. b Continuous Combined Hormone Therapy = 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate. c Cyclic Hormone Therapy = 0.625 mg conjugated estrogens for 28 days with concomitant 5 mg medroxyprogesterone acetate or 0.15 mg norgestrel on Days 1 through 14 or 17 through 28. d Includes only patients with an intact uterus: raloxifene hydrochloride, n=290; Hormone Therapy-Continuous Combined, n=67; Hormone Therapy-Cyclic, n=217. | |||
| Urogenital | |||
| Breast Pain | 4.4 | 37.5 | 29.7 |
| Vaginal Bleeding d | 6.2 | 64.2 | 88.5 |
| Digestive | |||
| Flatulence | 1.6 | 12.5 | 6.4 |
| Cardiovascular | |||
| Hot Flashes | 28.7 | 3.1 | 5.9 |
| Body as a Whole | |||
| Infection | 11 | 0 | 6.8 |
| Abdominal Pain | 6.6 | 10.4 | 18.7 |
| Chest Pain | 2.8 | 0 | 0.5 |
Warnings & Cautions for Raloxifene
Venous Thromboembolism
In clinical trials, raloxifene hydrochloride-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism). Other venous thromboembolic events also could occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with raloxifene hydrochloride than with placebo.
The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy. Because immobilization increases the risk for venous thromboembolic events independent of therapy, raloxifene hydrochloride should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride should be advised to move about periodically during prolonged travel.
The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure, superficial thrombophlebitis, and active malignancy.
Death Due to Stroke In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene hydrochloride. There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene hydrochloride versus 224 placebo ). Raloxifene hydrochloride had no significant effect on all-cause mortality.
The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking.
Cardiovascular Disease
Raloxifene hydrochloride should not be used for the primary or secondary prevention of cardiovascular disease. In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years.
Premenopausal Use There is no indication for premenopausal use of raloxifene hydrochloride. Safety of raloxifene hydrochloride in premenopausal women has not been established and its use is not recommended. Additionally, there is concern regarding inadvertent drug exposure in pregnancy in women of reproductive potential who become pregnant, due to risk of fetal harm.
Hepatic Impairment
Raloxifene hydrochloride should be used with caution in patients with hepatic impairment. Safety and efficacy have not been established in patients with hepatic impairment.
Concomitant Estrogen Therapy
The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended.
History of Hypertriglyceridemia when Treated with Estrogens
Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene hydrochloride. Women with this medical history should have serum triglycerides monitored when taking raloxifene hydrochloride.
History of Breast Cancer
Raloxifene hydrochloride has not been adequately studied in women with a prior history of breast cancer.
Raloxifene hydrochloride has not been adequately studied in men and its use is not recommended.
Unexplained Uterine Bleeding
Any unexplained uterine bleeding should be investigated as clinically indicated. Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial proliferation.
Breast Abnormalities
Any unexplained breast abnormality occurring during raloxifene hydrochloride therapy should be investigated. Raloxifene hydrochloride does not eliminate the risk of breast cancer.
Drug Interactions with Raloxifene
Cholestyramine
Concomitant administration of cholestyramine with raloxifene hydrochloride is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride should not be co-administered with other anion exchange resins.
Warfarin
If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride.
Other Highly Protein-Bound Drugs
Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins.
Systemic Estrogens
The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended.
Other Concomitant Medications
Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin. The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied.
Pregnancy Safety for Raloxifene
Pregnancy Risk Summary Raloxifene hydrochloride is contraindicated for use in pregnant women, and is not indicated for use in females of reproductive potential. Based on mechanism of action, raloxifene hydrochloride may block the important functions that estrogen has during all stages of pregnancy. Limited data with raloxifene hydrochloride use in pregnant women are insufficient to inform any drug associated risks for births defects or miscarriage.
In rabbits and rats dosed during organogenesis or during gestation and lactation, raloxifene hydrochloride produced multiple adverse reproductive and developmental effects, including abortion; fetal anomalies; and delayed or disrupted parturition leading to maternal and neonatal mortality, at doses less than or similar to the maximum recommended human dose (based on human body surface area comparison). Data Animal Data In the developmental and reproductive toxicity studies conducted with raloxifene hydrochloride, numerous adverse effects were observed in multiple animal species. In rabbits dosed during organogenesis, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m 2 ).
In rats dosed during organogenesis, retardation of fetal growth and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m 2 ). Treatment of rats during gestation and lactation with doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m 2 ) produced effects that included delayed and disrupted parturition, decreased neonatal survival and altered physical development, sex- and age-specific reductions in growth and changes in pituitary hormone content, and decreased lymphoid compartment size in offspring. At 10 mg/kg, the disruption of parturition resulted in maternal and progeny morbidity and death.
Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.
Pediatric Use of Raloxifene
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Contraindications for Raloxifene
Venous Thromboembolism
Raloxifene hydrochloride tablets are contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.
Pregnancy
Raloxifene hydrochloride is contraindicated for use in pregnancy, as it may cause fetal harm.
Overdosage Information for Raloxifene
In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride 600 mg/day was safely tolerated. In clinical trials, no raloxifene overdose has been reported. In postmarketing spontaneous reports, raloxifene overdose has been reported very rarely (less than 1 out of 10,000 patients treated).
The highest overdose has been approximately 1.5 grams. No fatalities associated with raloxifene overdose have been reported. Adverse reactions were reported in approximately half of the adults who took ≥180 mg raloxifene hydrochloride and included leg cramps and dizziness.
Two 18-month-old children each ingested raloxifene hydrochloride 180 mg. In these two children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase. There is no specific antidote for raloxifene.
Clinical Studies of Raloxifene
Treatment of Postmenopausal Osteoporosis Effect on Fracture Incidence The effects of raloxifene hydrochloride on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (MORE). All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures). The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures or b one or more baseline vertebral fractures.
Effect on Bone Mineral Density Raloxifene hydrochloride, 60 mg administered once daily, increased spine and hip BMD by 2 to 3%. All women in the study received calcium (500 mg/day) and vitamin D (400 to 600 IU/day). Raloxifene hydrochloride reduced the incidence of vertebral fractures whether or not patients had a vertebral fracture upon study entry.
The decrease in incidence of vertebral fracture was greater than could be accounted for by increase in BMD alone. Table 4: Effect of The mean percentage change in BMD from baseline for raloxifene hydrochloride was statistically significantly greater than for placebo at each skeletal site ( see Table 5). Table 5: Raloxifene Hydrochloride- (60 mg Once Daily) Related Increases in BMD a for the Osteoporosis Treatment Study Expressed as Mean Percentage Increase vs.
Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred. Such discontinuation was statistically significantly more frequent in the placebo group (3.7%) than in the raloxifene hydrochloride group (1.1%). Bone Histology Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment.
There were 56 paired biopsies evaluable for all indices. In raloxifene hydrochloride-treated patients, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover. Normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone after 2 years of treatment.
Effect on Endometrium Endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene hydrochloride-treated women had a 0.06 mm mean increase. Patients in the osteoporosis treatment study were not screened at baseline or excluded for pre-existing endometrial or uterine disease.
This study was not specifically designed to detect endometrial polyps. There was no difference between raloxifene hydrochloride- and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge.
Prevention of Postmenopausal Osteoporosis
The effects of raloxifene hydrochloride on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: a North American trial enrolled 544 women; a European trial, 601 women; and an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). The majority of the women were White (93.5%).
Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. Raloxifene hydrochloride, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD.
Effect on Bone Mineral Density Compared with placebo, the increases in BMD for each of the three studies were statistically significant at 12 months and were maintained at 24 months ( see Table 6). The placebo groups lost approximately 1% of BMD over 24 months. Table 6: Raloxifene Hydrochloride- (60 mg Once Daily) Related Increases in BMD a for the Three Osteoporosis Prevention Studies Expressed as Mean Percentage Increase vs.
The effects of raloxifene hydrochloride on forearm BMD were inconsistent between studies. In Study EU, raloxifene hydrochloride prevented bone loss at the ultradistal radius, whereas in Study NA, it did not ( see Figure 1). Effect on Endometrium In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months (for 24 months) by transvaginal ultrasonography (TVU).
A total of 2978 TVU measurements were collected from 831 women in all dose groups. Placebo-treated women had a 0.04 mm mean increase from baseline in endometrial thickness over 2 years, whereas the raloxifene hydrochloride-treated women had a 0.09 mm mean increase. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo.
There were no differences between the raloxifene and placebo groups with respect to the incidence of reported vaginal bleeding. Figure1
Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis MORE Trial The effect of raloxifene hydrochloride on the incidence of breast cancer was assessed as a secondary safety endpoint in a randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial in postmenopausal women. After 4 years, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo HR Raloxifene hydrochloride reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. Table 7 presents efficacy and selected safety outcomes.
CORE Trial The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial. Women were not re-randomized; the treatment assignment from the osteoporosis treatment trial was carried forward to this study. There was no reduction in the incidence of ER-negative breast cancer.
In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the raloxifene hydrochloride and placebo groups. In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned raloxifene hydrochloride (N=1355) compared with placebo (N=1286) (HR women-years); this was primarily due to a 65% reduction in the incidence of ER- positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. Table 7: Raloxifene Hydrochloride (60 mg Once Daily) vs.
Placebo on Outcomes in Postmenopausal Women with Osteoporosis RUTH Trial The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was assessed in a randomized, placebo-controlled, double-blind, multinational study in 10,101 postmenopausal women at increased risk of coronary events. Eighty-four percent were White, 9.8% of women reported a first-degree relative with a history of breast cancer, and 41.4% of the women had a 5-year predicted risk of invasive breast cancer ≥1.66%, based on the modified Gail model. Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 44% compared with placebo; this was primarily due to a 55% reduction in estrogen receptor (ER)-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo (ARR 1.2 per 1000 women-years).
Table 8 presents efficacy and selected safety outcomes. Table 8: Raloxifene Hydrochloride (60 mg Once Daily) vs. Placebo on Outcomes in Postmenopausal Women at Increased Risk for Major Coronary Events The effect of raloxifene hydrochloride in reducing the incidence of invasive breast cancer was consistent among women above or below age 65 or with a 5-year predicted invasive breast cancer risk, based on the modified Gail model, <1.66%, or ≥1.66%.
Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer STAR Trial The effects of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years on reducing the incidence of invasive breast cancer were assessed in 19,747 postmenopausal women in a randomized, double-blind trial conducted in North America by the National Surgical Adjuvant Breast and Bowel Project and sponsored by the National Cancer Institute. More than 93% of participants were White. Raloxifene hydrochloride was not superior to tamoxifen in reducing the incidence of invasive breast cancer.
The observed incidence rates of invasive breast cancer were raloxifene hydrochloride 4.4 and tamoxifen 4.3 per 1000 women per year. The results from a noninferiority analysis are consistent with raloxifene hydrochloride potentially losing up to 35% of the tamoxifen effect on reduction of invasive breast cancer. The effect of each treatment on invasive breast cancer was consistent when women were compared by baseline age, history of LCIS, history of atypical hyperplasia, 5-year predicted risk of breast cancer by the modified Gail model, or the number of relatives with a history of breast cancer.
Fewer noninvasive breast cancers occurred in the tamoxifen group compared to the raloxifene hydrochloride group. Table 9 presents efficacy and selected safety outcomes. Table 9: Raloxifene Hydrochloride (60 mg Once Daily) vs.
Tamoxifen (20 mg Once Daily) on Outcomes in Postmenopausal Women at Increased Risk for Invasive Breast Cancer.5 Effects on Cardiovascular Disease In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene hydrochloride 60 mg once daily for a median follow-up of 5.6 years. No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome). An increased risk of death due to stroke after treatment with raloxifene hydrochloride was observed: 59 (1.2%) raloxifene hydrochloride-treated women died due to a stroke compared to 9.
The incidence of stroke did not differ significantly between treatment groups ( 0 women-years).
| a Includes all patients with baseline and at least one follow-up radiograph. | ||||
| Number of Patients | Absolute Risk Reduction (ARR) | Relative Risk Reduction (95% CI) | ||
| Raloxifene Hydrochloride | Placebo | |||
| Fractures diagnosed radiographically | ||||
| Patients with no baseline fracture a | n=1401 | n=1457 | ||
| Number (%) of patients with ≥1 new vertebral fracture | 27 (1.9%) | 62 (4.3%) | 2.4% | 55% (29%, 71%) |
| Patients with ≥1 baseline fracture a | n=858 | n=835 | ||
| Number (%) of patients with ≥1 new vertebral fracture | 121 (14.1%) | 169 (20.2%) | 6.1% | 30% (14%, 44%) |
| Symptomatic vertebral fractures | ||||
| All randomized patients | n=2557 | n=2576 | ||
| Number (%) of patients with ≥1 new clinical (painful) vertebral fracture | 47 (1.8%) | 81 (3.1%) | 1.3% | 41% (17%, 59%) |
| a Note: all BMD increases were significant (p<0.001). b Intent-to-treat analysis; last observation carried forward. c All patients received calcium and vitamin D. d ND = not done (total body and radius BMD were measured only at 24 months). | |||
| Site | Time | ||
| 12 Months % | 24 Months % | 36 Months % | |
| Lumbar Spine | 2 | 2.6 | 2.6 |
| Femoral Neck | 1.3 | 1.9 | 2.1 |
| Ultradistal Radius | ND d | 2.2 | ND d |
| Distal Radius | ND d | 0.9 | ND d |
| Total Body | ND d | 1.1 | ND d |
| Site | Study | ||
|---|---|---|---|
| NA d % | EU d % | INT d,e % | |
| a Note: all BMD increases were significant (p≤0.001). b All patients received calcium. c Intent-to-treat analysis; last observation carried forward. d Abbreviations: NA = North American, EU = European, INT = International. e All women in the study had previously undergone hysterectomy. | |||
| Total Hip | 2 | 2.4 | 1.3 |
| Femoral Neck | 2.1 | 2.5 | 1.6 |
| Trochanter | 2.2 | 2.7 | 1.3 |
| Intertrochanter | 2.3 | 2.4 | 1.3 |
| Lumbar Spine | 2 | 2.4 | 1.8 |
| a CORE was a follow-up study conducted in a subset of 4011 postmenopausal women who originally enrolled in MORE. Women were not re-randomized; the treatment assignment from MORE was carried forward to this study. At CORE enrollment, the raloxifene hydrochloride group included 2725 total patients with 1355 patients who were originally assigned to raloxifene hydrochloride 60 mg once daily and 1370 patients who were originally assigned to raloxifene hydrochloride 120 mg at MORE randomization. b Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women; N/A = not applicable. c Included 1274 patients in placebo and 2716 patients in raloxifene hydrochloride who were not diagnosed with breast cancer prior to CORE enrollment. d p<0.05, obtained from the log-rank test, and not adjusted for multiple comparisons in MORE. e All cases were ductal carcinoma in situ. f Only patients with an intact uterus were included (MORE: placebo = 1999, raloxifene hydrochloride = 1950; CORE: placebo = 1008, raloxifene hydrochloride = 2138). | ||||||||||
| MORE 4 years | CORE a 4 years | |||||||||
| Outcomes | Placebo (N=2576) | Raloxifene Hydrochloride (N=2557) | HR (95% CI) b | Placebo (N=1286) | Raloxifene Hydrochloride (N=2725) | HR (95% CI) b | ||||
| n | IR b | n | IR b | n | IR b | n | IR b | |||
| Invasive c breast cancer | 38 | 4.36 | 11 | 1.26 | 0.29 (0.15, 0.56) d | 20 | 5.41 | 19 | 2.43 | 0.44 (0.24, 0.83) d |
| ER b, c positive | 29 | 3.33 | 6 | 0.69 | 0.2 (0.08, 0.49) | 15 | 4.05 | 12 | 1.54 | 0.37 (0.17, 0.79) |
| ER b, c negative | 4 | 0.46 | 5 | 0.57 | 1.23 (0.33, 4.6) | 3 | 0.81 | 6 | 0.77 | 0.95 (0.24, 3.79) |
| ER b, c unknown | 5 | 0.57 | 0 | 0 | N/A b | 2 | 0.54 | 1 | 0.13 | N/A b |
| Noninvasive c, e breast cancer | 5 | 0.57 | 3 | 0.34 | 0.59 (0.14, 2.47) | 2 | 0.54 | 5 | 0.64 | 1.18 (0.23, 6.07) |
| Clinical vertebral fractures | 107 | 12.27 | 62 | 7.08 | 0.57 (0.42, 0.78) | N/A b | N/A b | N/A b | N/A b | N/A b |
| Death | 36 | 4.13 | 23 | 2.63 | 0.63 (0.38, 1.07) | 29 | 7.76 | 47 | 5.99 | 0.77 (0.49, 1.23) |
| Death due to stroke | 6 | 0.69 | 3 | 0.34 | 0.49 (0.12, 1.98) | 1 | 0.27 | 6 | 0.76 | 2.87 (0.35, 23.8) |
| Stroke | 56 | 6.42 | 43 | 4.91 | 0.76 (0.51, 1.14) | 14 | 3.75 | 49 | 6.24 | 1.67 (0.92, 3.03) |
| Deep vein thrombosis | 8 | 0.92 | 20 | 2.28 | 2.5 (1.1, 5.68) | 4 | 1.07 | 17 | 2.17 | 2.03 (0.68, 6.03) |
| Pulmonary embolism | 4 | 0.46 | 11 | 1.26 | 2.76 (0.88, 8.67) | 0 | 0 | 9 | 1.15 | N/A b |
| Endometrial and uterine cancer f | 5 | 0.74 | 5 | 0.74 | 1.01 (0.29, 3.49) | 3 | 1.02 | 4 | 0.65 | 0.64 (0.14, 2.85) |
| Ovarian cancer | 6 | 0.69 | 3 | 0.34 | 0.49 (0.12, 1.95) | 2 | 0.54 | 2 | 0.25 | 0.47 (0.07, 3.36) |
| Hot flashes | 151 | 17.31 | 237 | 27.06 | 1.61 (1.31, 1.97) | 11 | 2.94 | 26 | 3.31 | 1.12 (0.55, 2.27) |
| Peripheral edema | 134 | 15.36 | 164 | 18.73 | 1.23 (0.98, 1.54) | 30 | 8.03 | 61 | 7.77 | 0.96 (0.62, 1.49) |
| Cholelithiasis | 45 | 5.16 | 53 | 6.05 | 1.18 (0.79, 1.75) | 12 | 3.21 | 35 | 4.46 | 1.39 (0.72, 2.67) |
| a Note: There were a total of 76 breast cancer cases in the placebo group and 52 in the raloxifene hydrochloride group. For two cases, one in each treatment group, invasive status was unknown. b Abbreviations: CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; IR = annual incidence rate per 1000 women. c p<0.05, obtained from the log-rank test, after adjusting for the co-primary endpoint of major coronary events. d All cases were ductal carcinoma in situ. e Only patients with an intact uterus were included (placebo = 3882, raloxifene hydrochloride = 3900). f Only patients with at least one ovary were included (placebo = 4606, raloxifene hydrochloride = 4559). g Only patients with an intact gallbladder at baseline were included (placebo = 4111, raloxifene hydrochloride = 4144). | |||||
| Outcomes | Placebo a (N=5057) | Raloxifene Hydrochloride a (N=5044) | HR (95% CI) b | ||
| n | IR b | n | IR b | ||
| Invasive breast cancer | 70 | 2.66 | 40 | 1.5 | 0.56 (0.38, 0.83) c |
| ER b positive | 55 | 2.09 | 25 | 0.94 | 0.45 (0.28, 0.72) |
| ER b negative | 9 | 0.34 | 13 | 0.49 | 1.44 (0.61, 3.36) |
| ER b unknown | 6 | 0.23 | 2 | 0.07 | 0.33 (0.07, 1.63) |
| Noninvasive d breast cancer | 5 | 0.19 | 11 | 0.41 | 2.17 (0.75, 6.24) |
| Clinical vertebral fractures | 97 | 3.7 | 64 | 2.4 | 0.65 (0.47, 0.89) |
| Death | 595 | 22.45 | 554 | 20.68 | 0.92 (0.82, 1.03) |
| Death due to stroke | 39 | 1.47 | 59 | 2.2 | 1.49 (1, 2.24) |
| Stroke | 224 | 8.6 | 249 | 9.46 | 1.1 (0.92, 1.32) |
| Deep vein thrombosis | 47 | 1.78 | 65 | 2.44 | 1.37 (0.94, 1.99) |
| Pulmonary embolism | 24 | 0.91 | 36 | 1.35 | 1.49 (0.89, 2.49) |
| Endometrial and uterine cancer e | 17 | 0.83 | 21 | 1.01 | 1.21 (0.64 to 2.3) |
| Ovarian cancer f | 10 | 0.41 | 17 | 0.7 | 1.69 (0.78, 3.7) |
| Hot flashes | 241 | 9.09 | 397 | 14.82 | 1.68 (1.43, 1.97) |
| Peripheral edema | 583 | 22 | 706 | 26.36 | 1.22 (1.09, 1.36) |
| Cholelithiasis g | 131 | 6.2 | 168 | 7.83 | 1.26 (1.01, 1.59) |
| a Abbreviations: CI = confidence interval; DCIS = ductal carcinoma in situ; ER = estrogen receptor; IR = annual incidence rate per 1000 women; LCIS = lobular carcinoma in situ; RR = risk ratio for women in the raloxifene hydrochloride group compared with those in the tamoxifen group. b Of the 60 noninvasive breast cases in the tamoxifen group, 5 were mixed types. Of the 83 noninvasive breast cancers in the raloxifene group, 7 were mixed types. c Only patients with an intact uterus at baseline were included (tamoxifen = 4739, raloxifene hydrochloride = 4715). d Only patients with at least one intact ovary at baseline were included (tamoxifen = 6813, raloxifene hydrochloride = 6787). e Defined as myocardial infarction, severe angina, or acute ischemic syndromes. f Only patients who were free of cataracts at baseline were included (tamoxifen = 8342, raloxifene hydrochloride = 8333). g Peripheral edema events are included in the term edema. | |||||
| Outcomes | Raloxifene Hydrochloride (N=9751) | Tamoxifen (N=9736) | RR (95% CI) a | ||
| n | IR a | n | IR a | ||
| Invasive breast cancer | 173 | 4.4 | 168 | 4.3 | 1.02 (0.82, 1.27) |
| ER a positive | 115 | 2.93 | 120 | 3.07 | 0.95 (0.73, 1.24) |
| ER a negative | 52 | 1.32 | 46 | 1.18 | 1.12 (0.74, 1.71) |
| ER a unknown | 6 | 0.15 | 2 | 0.05 | 2.98 (0.53, 30.21) |
| Noninvasive breast cancer b | 83 | 2.12 | 60 | 1.54 | 1.38 (0.98, 1.95) |
| DCIS a | 47 | 1.2 | 32 | 0.82 | 1.46 (0.91, 2.37) |
| LCIS a | 29 | 0.74 | 23 | 0.59 | 1.26 (0.7, 2.27) |
| Uterine cancer c | 23 | 1.21 | 37 | 1.99 | 0.61 (0.34, 1.05) |
| Endometrial hyperplasia c | 17 | 0.9 | 100 | 5.42 | 0.17 (0.09, 0.28) |
| Hysterectomy c | 92 | 4.84 | 246 | 13.25 | 0.37 (0.28, 0.47) |
| Ovarian cancer d | 18 | 0.66 | 14 | 0.52 | 1.27 (0.6, 2.76) |
| Ischemic heart disease e | 138 | 3.5 | 125 | 3.19 | 1.1 (0.86, 1.41) |
| Stroke | 54 | 1.36 | 56 | 1.42 | 0.96 (0.65, 1.42) |
| Deep vein thrombosis | 67 | 1.69 | 92 | 2.35 | 0.72 (0.52, 1) |
| Pulmonary embolism | 38 | 0.96 | 58 | 1.47 | 0.65 (0.42, 1) |
| Clinical vertebral fractures | 58 | 1.46 | 58 | 1.47 | 0.99 (0.68, 1.46) |
| Cataracts f | 343 | 10.34 | 435 | 13.19 | 0.78 (0.68, 0.91) |
| Cataract surgery f | 240 | 7.17 | 295 | 8.85 | 0.81 (0.68, 0.96) |
| Death | 104 | 2.62 | 109 | 2.76 | 0.95 (0.72, 1.25) |
| Edema g | 741 | 18.66 | 664 | 16.83 | 1.11 (1, 1.23) |
| Hot flashes | 6748 | 169.91 | 7170 | 181.71 | 0.94 (0.9, 0.97) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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