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Raloxifene
EVISTA® (raloxifene hydrochloride) is a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[ 4-[ 2-( 1-piperidinyl) ethoxy] phenyl]-, hydrochloride. Raloxifene hydrochloride (HCl) has the empirical formula C28H27NO4S • HCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl is an off-white to pale-yellow solid that is very slightly soluble in water. EVISTA is supplied in a tablet
dosage form
for oral administration.
Each EVISTA tablet contains
60 mg of raloxifene HCl,
which is the molar equivalent of 55.71 mg
of free base. Inactive ingredients include anhydrous lactose, carnauba
wax, crospovidone, FD& C Blue No. 2 aluminum
lake, hydroxypropyl methylcellulose, lactose
monohydrate, magnesium
stearate, modified pharmaceutical
glaze, polyethylene
glycol, polysorbate 80, povidone, propylene glycol, and titanium
dioxide.
Mechanism of Action Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. This imbalance between resorption and formation is related to loss of estrogen, and may also involve age-related impairment of osteoblasts or their precursors. Raloxifene reduces resorption of bone and decreases overall bone turnover. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers, evidence from radiocalcium kinetics studies for decreased bone resorption and increases in bone mineral density (BMD). Raloxifene’s biological actions, like those of estrogen, are mediated through binding to estrogen receptors. This binding results in differential expression of multiple estrogen-regulated genes in different tissues. Recent data suggest that the estrogen receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or gene-specific. Clinical data indicate that raloxifene, a selective estrogen receptor modulator (SERM), has estrogen-like effects on bone (increase in BMD) and on lipid (decrease in total and LDL cholesterol levels) metabolism. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. Preliminary clinical data (through 30 months) suggest EVISTA lacks estrogen-like effects on uterus and breast tissue. Pharmacokinetics The disposition of raloxifene has been evaluated in 276 postmenopausal women in conventional clinical pharmacology studies and in more than 1300 postmenopausal women in selected raloxifene trials. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters. Table1 summarizes the pharmacokinetic parameters of raloxifene. Absorption Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2.0%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene (C max 28% and AUC 16%), but does not lead to clinically meaningful changes in systemic exposure. EVISTA can be administered without regard to meals. Distribution Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/kg and is not dose dependent. Raloxifene and the monoglucuronide conjugates are highly bound to plasma proteins. Raloxifene binds to both albumin and D 1-acid glycoprotein, but not to sex steroid binding globulin. In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen to plasma proteins. Metabolism Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 14 C-labeled raloxifene. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4'-diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites. Following intravenous administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kg •hr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing. Results from single oral doses of raloxifene predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kg •hr. Increasing doses of raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC). Excretion Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine . Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates. In the osteoporosis prevention trials, raloxifene and metabolite concentrations are similar for women with estimated creatinine clearance as low as 23 mL/min. Table 1.
a Data normalized for dose in mg and body weight in kg. b Range of observed half-life. Special Populations Geriatric : No differences in raloxifene pharmacokinetics were detected with regard to age (range 42 to 84 years). Pediatric : The pharmacokinetics of raloxifene have not been evaluated in a pediatric population. Gender : Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched female and male volunteers. Race : Pharmacokinetic differences due to race have been studied on a limited basis in 1053 women consisting of 93.5% Caucasian, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the osteoporosis prevention trials. There were no discernible differences in raloxifene plasma concentrations among these groups; however, the influence of race cannot be effectively determined. Renal Insufficiency: Since negligible amounts of raloxifene are eliminated in urine, a study in patients with renal insufficiency was not conducted. Hepatic Dysfunction : Raloxifene was studied, as a single dose, in Child-Pugh Class A patients with cirrhosis and total serum bilirubin ranging from 0.6 to 2.0 mg/dL. Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with bilirubin concentrations. Safety and efficacy have not been evaluated further in patients with hepatic insufficiency (see WARNINGS). Drug-Drug Interactions Clinically significant drug-drug interactions are discussed in PRECAUTIONS. Ampicillin: Peak concentrations of raloxifene and the overall extent of absorption are reduced 28% and 14%, respectively, with coadministration of ampicillin. These reductions are consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene were not affected. Therefore, EVISTA can be concurrently administered with ampicillin. Antacids: Concurrent administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. Corticosteroids: The coadministration of EVISTA with corticosteroids has not been evaluated. Cyclosporine: The coadministration of EVISTA with cyclosporine has not been evaluated. Digoxin: Raloxifene has no effect on the pharmacokinetics of digoxin. 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, equivalent at the bone level to approximately 6 years in humans. Raloxifene and estrogen increased BMD, but variability among animals obscured the ability to detect effects of either treatment on biomechanical strength. However, bone strength was positively correlated to BMD in both raloxifene-and estrogen-treated monkeys, indicating that BMD is a reasonable marker for bone strength. 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 EVISTA’s action as a skeletal antiresorptive agent. Clinical Studies Effects on Total Body and Regional Bone Mineral Density In postmenopausal women, EVISTA preserves bone mass and increases BMD relative to calcium alone at 24 months. The effect on hip bone mass is similar to that for the spine. The relationships of BMD changes to skeletal fracture rates have not yet been established in EVISTA-treated women. The effects of EVISTA on BMD in postmenopausal women were examined in three large 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 bone mineral density 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 3 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 versus 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 3 studies were statistically significant at 12 months and were maintained at 24 months (Table 2). The calcium-supplemented placebo groups lost approximately 1% of BMD over 24 months. (See figures below for total hip results.) Table 2.
a Intent-to-treat analysis; last observation carried forward. b 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 two 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 the osteoporosis 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 24-month observation period. Bone Histomorphometry 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 8 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 versus 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. In a blinded ongoing study, light microscopic evaluation of transiliac biopsies taken at baseline and after 2 years of therapy in 59 postmenopausal women receiving placebo, 60 mg-, or 120 mg-raloxifene hydrochloride showed no osteomalacia, osteocyte damage, woven bone, marrow fibrosis, or other abnormalities. 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 3). EVISTA decreased serum total and LDL cholesterol without effects on serum total HDL cholesterol or triglycerides. In addition, EVISTA significantly decreased serum fibrinogen and lipoprotein (a). Table 3.
a Significantly different from placebo (p< 0.05). b Significantly different from HRT (p< 0.05). In the osteoporosis prevention studies (N= 1764), 24-month data were consistent with results from the 6-month study. Compared with placebo, EVISTA significantly decreased serum total and LDL cholesterol by approximately 5% and 8% respectively, but did not affect HDL cholesterol or triglycerides. Effects on the Uterus 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. 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. 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,Table
5).
EVISTA is indicated for the prevention of osteoporosis in postmenopausal women. The effects of EVISTA on fracture risk are not yet known. Supplemental calcium should be added to the diet if daily intake is inadequate. No single clinical finding or test result can quantify risk of postmenopausal osteoporosis with certainty. However, clinical assessment can help to identify women at increased risk. Widely accepted risk factors include Caucasian or Asian descent, slender body b.i.d. early estrogen deficiency, smoking, alcohol consumption, low calcium diet, sedentary lifestyle, and family history of osteoporosis. Evidence of increased bone turnover from serum and urine markers and low bone mass (e. g., at least 1 standard deviation below the mean for healthy, young adult women) as determined by densitometric techniques are also predictive. The greater the number of clinical risk factors, the greater the probability of developing postmenopausal osteoporosis.
The recommended dosage is one 60-mg EVISTA tablet daily which may be administered any time of day without regard to meals. The effect of EVISTA on BMD beyond two years of treatment is not known at this time, but is being evaluated in ongoing clinical trials. HOW SUPPLIED EVISTA 60-mg tablets are white, elliptical, and film coated. They are imprinted on one side with LILLY and the tablet code 4165 in edible blue ink. They are available as follows:
CAUTION — Federal (USA) law
prohibits dispensing without prescription.
The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin replacement therapy (HRT) control groups. The duration of treatment ranged from 2 to 30 months and 2036 women were exposed to raloxifene (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day). The majority of adverse events occurring during clinical trials were mild and generally did not require discontinuation of therapy. Therapy was discontinued due to an adverse event in 11.4% of 581 EVISTA-treated women and 12.2% of 584 placebo-treated women. Common adverse events considered to be drug-related were hot flashes and leg cramps (see Table 4). The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment. Discontinuation rates due to hot flashes did not differ significantly between EVISTA and placebo groups (1.7% and 2.2%, respectively). Adverse Events in Placebo-controlled Clinical Trials Table 4 lists adverse events occurring in the placebo-controlled clinical trial database at a frequency ³2.0% in either group and in more EVISTA-treated women than in placebo-treated women. Adverse events are shown without attribution of causality. Table 4.
Comparison of EVISTA and Hormone Replacement Therapy Adverse Events EVISTA was compared with estrogen-progestin replacement therapy (HRT) in 3 clinical trials. Table 5 shows adverse events occurring more frequently in one treatment group and at an incidence ³2.0% in any group. Adverse events are shown without attribution of causality.
bTreatment-emergent uterine-related adverse event, including only patients with an intact uterus: EVISTA, n= 290, HRT-Continuous Combined, n= 67, HRT-Cyclic, n= 217. Continuous Combined HRT = 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate. Cyclic HRT = 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. Laboratory Changes The following changes in analyte concentrations are commonly observed during EVISTA therapy: increased apolipoprotein A1; and reduced serum total cholesterol, LDL cholesterol, fibrinogen, apolipoprotein B, and lipoprotein (a). EVISTA modestly increases hormone-binding globulin concentrations, including sex steroid-binding globulin, thyroxine-binding globulin, and corticosteroid-binding globulin with corresponding increases in measured total hormone concentrations. There is no evidence that these changes in hormone-binding globulin concentrations affect concentrations of the corresponding free hormones. There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin which were generally of lesser magnitude than decreases observed during ERT/HRT. Platelet count was also decreased slightly and was not different from ERT. Additional Safety INFORMATION Incidences of estrogen-dependent carcinoma of the endometrium and breast are being evaluated across all completed and ongoing clinical trials involving 12,802 patients, of which approximately 8300 women have received at least one dose of raloxifene. The duration of exposure has been up to 39 months. Endometrium: Compared to placebo, raloxifene did not increase the risk of endometrial cancer. Breast: Compared to placebo, raloxifene did not increase the risk of breast cancer.
Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY,
Drug-Drug Interactions
Venous Thromboembolic Events: An analysis of EVISTA-treated women across all placebo-controlled clinical trials showed an increased risk of venous thromboembolic events defined as deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. The greatest risk for thromboembolic events occurs during the first 4 months of treatment. EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization (e. g., post-surgical recovery, prolonged bed rest), and EVISTA therapy should be resumed only after the patient is fully ambulatory. Patients should be advised to avoid prolonged restrictions of movement during travel. The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure and active malignancy. Premenopausal Use: There is no indication for premenopausal use of EVISTA. Safety of EVISTA in premenopausal women has not been established and its use is not recommended (see CONTRAINDICATIONS). Hepatic Dysfunction: Raloxifene was studied, as a single dose, in Child-Pugh Class A patients with cirrhosis and serum total bilirubin ranging from 0.6 to 2.0 mg/dL. Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with total bilirubin concentrations. Safety and efficacy have not been evaluated further in patients with severe hepatic insufficiency.
General Concurrent Estrogen Therapy: The concurrent use of EVISTA and systemic estrogen or hormone replacement therapy (ERT or HRT) has not been studied in prospective clinical trials and therefore concomitant use of EVISTA with systemic estrogens is not recommended. Lipid Metabolism: EVISTA lowers serum total and LDL cholesterol by 6% to 11%, but does not affect serum concentrations of total HDL cholesterol or triglycerides. These effects should be taken into account in therapeutic decisions for patients who may require therapy for hyperlipidemia. Concurrent use of EVISTA and lipid-lowering agents has not been studied. Endometrium: EVISTA has not been associated with endometrial proliferation (see CLINICAL PHARMACOLOGY Clinical Studies and ADVERSE REACTIONS). Unexplained uterine bleeding should be investigated as clinically indicated. Breast: EVISTA has not been associated with breast enlargement, breast pain, or an increased risk of breast cancer (see CLINICAL PHARMACOLOGY Clinical Studies and ADVERSE REACTIONS). Any unexplained breast abnormality occurring during EVISTA therapy should be investigated. History of Breast Cancer: EVISTA has not been adequately studied in women with a prior history of breast cancer. Use in Men: Safety and efficacy have not been evaluated in men. Patient INFORMATION See PATIENT INFORMATION section. Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis: In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors in female animals given 9 to 242 mg/kg, which included benign and malignant tumors of granulosa/theca cell origin and benign tumors of epithelial cell origin. Systemic exposure (AUC) of raloxifene in this group was 0.3 to 34 times that in postmenopausal women administered a 60-mg dose. There was also an increased incidence of testicular interstitial cell tumors and prostatic adenomas and adenocarcinomas in males given 41 or 210 mg/kg (4.7 or 24 times the AUC in humans), and prostatic leiomyoblastoma in males given 210 mg/kg. In a 2-year carcinogenicity study in rats, an increased incidence in ovarian tumors of granulosa/theca cell origin was observed in females given 279 mg/kg (approximately 400 times the AUC in humans). The female rodents in these studies were treated during their reproductive lives when their ovaries were functional and responsive to hormonal stimulation. The clinical relevance of these tumor findings is not known. Mutagenesis: Raloxifene HCl was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis 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 in vivo sister chromatid exchange assay in Chinese hamsters, and the in vivo micronucleus test in mice. Impairment of Fertility: When male and female rats were given daily doses ³5 mg/kg (³0.8 times the human dose based on surface area, mg/m2) prior to and during mating, no pregnancies occurred. In male rats, daily doses up to 100 mg/kg (16 times the human dose based on surface area, mg/m2 ) for at least 2 weeks did not affect sperm production or quality, or reproductive performance. In female rats, at doses of 0.1 to 10 mg/kg/day (0.02 to 1.6 times the human dose based on surface area, mg/m2), raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. In another study in rats in which raloxifene was given during the preimplantation period at doses ³ 0.1 mg/kg (³ 0.02 times the human dose based on surface area, mg/m2), raloxifene delayed and disrupted embryo implantation resulting in prolonged gestation and reduced litter size. The reproductive and developmental effects observed in animals are consistent with the estrogen receptor activity of raloxifene. Pregnancy Pregnancy Category X: EVISTA should not be used in women who are or may become pregnant (see CONTRAINDICATIONS). Nursing Mothers: EVISTA should not be used by lactating women (see CONTRAINDICATIONS). It is not known whether raloxifene is excreted in human milk. Pediatric Use: EVISTA should not be used in pediatric patients. See also DRUG INTERACTIONS
and PATIENT INFORMATION.
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