|
Antacids — Concurrent administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. Corticosteroids — The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose. Cholestyramine — See PRECAUTIONS. Text Continues Below
Cyclosporine — The co-administration of EVISTA with cyclosporine has not been evaluated. Digoxin — Raloxifene has no effect on the pharmacokinetics of digoxin.
Warfarin — See PRECAUTIONS. ANIMAL PHARMACOLOGY The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover, and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine. Histologic examination of bone from rats and monkeys treated with raloxifene showed no evidence of woven bone, marrow fibrosis, or mineralization defects. These results are consistent with data from human studies of radiocalcium kinetics and markers of bone metabolism, and are consistent with the action of EVISTA as a skeletal antiresorptive agent. CLINICAL STUDIES In postmenopausal women with osteoporosis, EVISTA reduced the risk of vertebral fractures. EVISTA also increased BMD of the spine, hip, and total body. Similarly, in early postmenopausal women without osteoporosis (women with normal or low BMD without fracture), EVISTA increased spine, hip, and total body BMD relative to calcium alone at 24 months. The effect on hip bone mass was similar to that for the spine. Treatment of Osteoporosis The effects of EVISTA 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. 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. Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years. EVISTA, 60 mg administered once daily, increased spine and hip BMD by 2 to 3%. EVISTA decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for EVISTA (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for EVISTA (relative risk reduction = 30%) (Table 2). All women in the study received calcium (500 mg/ day) and vitamin D (400 to 600 IU/ day). EVISTA 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 2. Effect of EVISTA on Risk of Vertebral Fractures Number of Patients Absolute Risk
Reduction Relative Risk Reduction (95% CI)
EVISTA 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
Includes all patients with baseline and at least one follow-up radiograph. The mean percentage change in BMD from baseline for EVISTA was statistically significantly greater than for placebo at each skeletal site (Table 3). Table 3. EVISTA (60 mg Once Daily) Related Increases in BMD for the Osteoporosis Treatment Study Expressed as Mean Percentage Increase vs. Placebo ab
Time Site 12 Months % 24 Months % 36 Months % Lumbar Spine 2.0 2.6 2.6
Femoral Neck 1.3 1.9 2.1 Ultradistal Radius ND 2. 2 ND
Distal Radius ND 0. 9 ND Total Body ND 1.1 ND
Note: all BMD increases were significant (p< 0.001). a Intent-to-treat analysis; last observation carried forward.
b All patients received calcium and vitamin D.
ND= not done (total body and radius BMD were measured only at 24 months). 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 EVISTA group (1.1%). Prevention of Osteoporosis The effects of EVISTA on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/ day). Women enrolled in these studies had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause). The majority of the women were Caucasian (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 studies ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. EVISTA, 60 mg administered once daily, produced increases in bone mass vs. calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD. 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 (Table 4). The placebo groups lost approximately 1% of BMD over 24 months. Table 4. EVISTA (60 mg Once Daily) Related Increases in BMD for the Three Osteoporosis Prevention Studies Expressed as Mean Percentage Increase vs. Placebo a at 24 Months b
Study
Site NA % EU % INT
c
% Total Hip 2.0 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 2.0 2.4 1.8
Abbreviations: NA = North American, EU = European, INT = International. Note: all BMD increases were significant (p 0.001).
a All patients received calcium.
b Intent-to-treat analysis; last observation carried forward.
c All women in the study had previously undergone hysterectomy.
EVISTA also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward's Triangle (hip) by 3.1% to 4.0%. The effects of EVISTA on forearm BMD were inconsistent between studies. In Study EU, EVISTA prevented bone loss at the ultradistal radius, whereas in Study NA, it did not. Assessments of Bone Turnover In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily EVISTA 60 mg, cyclic estrogen/ progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month [HRT]), or no treatment. Treatment with either EVISTA or HRT was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/ day and +60 mg Ca/ day, respectively, for EVISTA and -162 mg Ca/ day and +91 mg Ca/ day, respectively, for HRT). In both the osteoporosis treatment and prevention trials, EVISTA therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e. g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods. Bone Histomorphometry In the treatment study, 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 EVISTA-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. The tissue-and cellular-level effects of raloxifene were assessed by histomorphometric evaluation of human iliac crest bone biopsies taken after administration of a fluorochrome substance to label areas of mineralizing bone. The effects of EVISTA on bone histomorphometry were determined by pre-and post-treatment biopsies in a 6-month study of Caucasian postmenopausal women who received once-daily doses of EVISTA 60 mg or 0.625 mg conjugated estrogens. Ten raloxifene-treated and eight estrogen-treated women had evaluable bone biopsies at baseline and after 6 months of therapy. Bone formation rate/ bone volume and activation frequency, the primary efficacy parameters, decreased to a greater extent with conjugated estrogen treatment vs. EVISTA treatment, although the differences were not statistically significant. Bone in EVISTA-and estrogen-treated women showed no evidence of mineralization defects, woven bone, or marrow fibrosis. Effects on Lipid Metabolism The effects of EVISTA on selected lipid fractions and clotting factors were evaluated in a 6-month study of 390 postmenopausal women. EVISTA was compared with oral continuous combined estrogen/ progestin (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate, [HRT]) and placebo (Table 5). EVISTA decreased serum total and LDL cholesterol without effects on serum total HDL cholesterol or triglycerides. In addition, EVISTA statistically significantly decreased serum fibrinogen and lipoprotein (a). Table 5. EVISTA (60 mg Once Daily) and Oral HRT Effects on Selected Lipid Fractions and Clotting Factors in a 6-Month study — Median Percentage Change from Baseline
Treatment Group Endpoint
EVISTA (N= 95)
%
HRT (N= 96)
%
PLACEBO (N= 98)
% Total Cholesterol -6. 6 a -4. 4 a 0.9
LDL Cholesterol -10.9 a -12.7 a 1.0 HDL Cholesterol 0. 7 b 10.6 a 0.9
HDL-2 Cholesterol 15.4 b 33.3 a 0.0 HDL-3 Cholesterol -2. 5 ab 2.7 0.0
Fibrinogen -12.2 ab -2. 8 -2. 1 Lipoprotein (a) -4. 1 ab -16.3 a 3.3
Triglycerides -4. 1 b 20.0 a -0. 3 Plasminogen Activator Inhibitor-1 -2. 1 b -29.0 a -9. 4
Abbreviations: HRT = continuous combined estrogen/ progestin (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate).
a Significantly different from placebo (p< 0.05).
b Significantly different from HRT (p< 0. 05). Consistent with results from the 6-month study, in the osteoporosis treatment (36 months) and prevention (24 months) studies, EVISTA statistically significantly decreased serum total and LDL cholesterol by 5% to 6% and 8% to 10%, respectively, compared to placebo. EVISTA did not affect HDL cholesterol or triglyceride levels. The effect of EVISTA-induced reductions in total and LDL cholesterol on risk for cardiovascular disease is currently under study. Effects on the Uterus In the osteoporosis treatment trial, 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 EVISTA-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. Over the 36 months of the study, clinically or histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 EVISTA-treated women, and in 31 of 2010 women treated with raloxifene HCl 120 mg/ day. There was no difference between EVISTA-and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge. 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 EVISTA-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. In a 6-month study of 18 postmenopausal women that compared EVISTA to conjugated estrogens (0.625 mg/ day [ERT]), endpoint endometrial biopsies demonstrated stimulatory effects of ERT, which were not observed for EVISTA. All samples from EVISTA-treated women showed nonproliferative endometria. A 12-month study of uterine effects compared a higher dose of raloxifene HCl (150 mg/ day) with HRT. At baseline, 43 raloxifene-treated postmenopausal women and 37 HRT-treated women had a nonproliferative endometrium. At study completion, endometria in all of the raloxifene-treated women remained nonproliferative whereas 13 HRT-treated women had developed proliferative changes. Also, HRT significantly increased uterine volume; raloxifene did not increase uterine volume. Thus, no stimulatory effect of raloxifene on the endometrium was detected at more than twice the recommended dose. Compared to placebo, EVISTA did not increase the risk of ovarian carcinoma. Effects on the Breast Across all placebo-controlled trials, EVISTA was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. EVISTA was associated with significantly less breast pain and tenderness than reported by women receiving estrogens with or without added progestin (see ADVERSE REACTIONS and Table 6). Mammograms were routinely performed on an annual or biennial basis in all placebo-controlled clinical trials lasting at least 12 months. Independent review has determined that 25 cases (raloxifene and placebo combined) represented newly-diagnosed invasive breast cancer. Among 7108 women randomized to raloxifene, there were 10 cases of invasive breast cancer per 19,381 person-years of follow-up (0.52 per 1000). Among 3467 women randomized to placebo, there were 15 cases of invasive breast cancer per 9250 person-years of follow-up (1.62 per 1000). The effectiveness of raloxifene in reducing the risk of breast cancer has not been established. Page: << Prev | 1 | 2 | 3 | 4 | 5
|
.gif)
