Selective Estrogen Receptor Modulator
Action And Clinical Pharmacology: Raloxifene is a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The SERM profile of raloxifene includes estrogen agonist effects on bone and lipid metabolism but not in uterine or breast tissues.
Pharmacokinetics: The disposition of raloxifene has been evaluated in 276 postmenopausal women in conventional clinical pharmacology studies and in more than 1 300 postmenopausal women in selected raloxifene trials. Raloxifene exhibits high within-subject variability (approximately 30%) of most pharmacokinetic parameters. Table I 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%. 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 with a standardized, high-fat meal increases the absorption of raloxifene slightly, but does not lead to clinically meaningful changes in systemic exposure. Raloxifene can be administered without regard to meals.
Distribution: Following oral administration of single doses ranging from 30 to 150 mg of raloxifene, the apparent volume of distribution is 2 348 L/kg and is not dose dependent.
Raloxifene and the monoglucuronide conjugates are highly bound to plasma proteins. Raloxifene binds to both albumin and a1-acid glycoprotein, but not to sex steroid binding globulin. In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen.
Metabolism: Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 4-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 portion of the plasma concentration curve for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites.
Following i.v. administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kg.h. 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/kgÂh. Increasing doses of raloxifene (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; negligible amounts are 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.
Special Populations: Geriatrics: The pharmacokinetics of raloxifene are independent of age (42 to 83 years).
Children: 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 male and female volunteers.
Race: Pharmacokinetic differences due to race have been studied on a limited basis in 1 053 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.
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 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 Precautions).
Drug Interactions: Clinically significant drug-interactions are discussed in Precautions.
Ampicillin: Peak concentrations of raloxifene are reduced with coadministration of ampicillin. The reduction in peak concentrations is consistent with reduced enterohepatic cycling associated with antibiotic reduction of enteric bacteria. Since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene 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.
Digoxin: Raloxifene has no effect on the pharmacokinetics of digoxin.
The influence of concomitant medication on raloxifene plasma concentrations was evaluated in the osteoporosis prevention trials. Frequently coadministered drugs included: acetaminophen, nonsteroidal anti-inflammatory drugs (such as ASA, ibuprofen and naproxen), oral antibiotics, H1 antagonists, H2 antagonists and benzodiazapines. No clinically relevant effects of the coadministration of the agents on raloxifene disposition were identified.
Pharmacodynamics: General: Postmenopausal women have an increased risk of chronic illnesses such as osteoporosis and atherosclerotic cardiovascular disease resulting from estrogen deficiency. Estrogen replacement reduces the risk of osteoporosis and coronary artery disease, but it also increases the risk of endometrial carcinoma and possibly breast cancer. The selective estrogen receptor modulator (SERM) profile of raloxifene includes estrogen agonist effects on bone and lipid metabolism, and estrogen antagonist effects in uterine and breast tissues. Thus, raloxifene provides an alternative to estrogen replacement therapy for prevention of postmenopausal osteoporosis.
Raloxifene’s biological actions, like those of estrogen, are mediated through high-affinity binding to estrogen receptors and regulation of gene expression. 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 2 distinct pathways which are ligand-, tissue- and/or gene-specific.
Effects on the Skeleton: During early to middle adult life, bone undergoes continuous remodeling. In this process, local areas of bone resorption are refilled completely by ensuing bone formation; that is, resorption and formation are in balance. The result is that bone mass remains relatively constant. Ovarian estrogen is important for maintenance of this balance in bone turnover. Marked decreases in estrogen availability, such as after oophorectomy or menopause, lead to marked increases in bone resorption. After menopause, bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses.
This imbalance between resorption and formation may be related to loss of estrogen, or to age-related impairment of osteoblasts or their precursors. Estrogen replacement therapy reduces resorption of bone by inhibiting the formation and action of osteoclasts and decreases overall bone turnover. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers, histologic evidence of decreased bone resorption and formation, and increased bone mineral density (BMD). Although raloxifene increases BMD to a lesser extent than estrogen, the effects of raloxifene on bone turnover in postmenopausal women parallel those of estrogen, as shown by studies of bone mineral densitometry, radiocalcium kinetics, bone markers and bone histomorphometry.
Effects on Total Body and Regional Bone Mineral Density: The effects of raloxifene on BMD in postmenopausal women were examined in 3 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). Raloxifene, 60 mg administered once daily, produced significant 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. The increases in BMD were statistically significant at 12 months and were maintained at 24 months (see Table II). In contrast, the calcium-supplemented placebo groups lost approximately 1% of BMD over 24 months.
Raloxifene also increased BMD compared with placebo in the total body by 1.3% to 2% and in Ward’s Triangle (hip) by 3.1% to 4%. In the international trial, conjugated equine estrogen 0.625 mg/day (ERT) was used as an active comparator. The mean increases in BMD at 24 months for estrogen compared with placebo were: lumbar spine, 5.4%; total hip, 2.9%.
Thus, in postmenopausal women, raloxifene preserves bone mass and increases BMD significantly relative to calcium alone at 24 months. The effect on hip bone mass is similar to that for the spine.
In an interim analysis of a study on 7 705 postmenopausal women with osteoporosis (mean age 66.5 years), raloxifene therapy for 2 years reduced the incidence of vertebral fractures by 34% (95% confidence interval, 15% to 48% reduction) in women with prevalent fractures and by 52% (95% confidence interval, 16% to 72% reduction) in women without prevalent fractures. The effect of raloxifene in reducing the incidence of nonvertebral fracture is not yet known.
Assessments of Bone Turnover: In a 31-week radiocalcium kinetics study, raloxifene was associated with reduced bone resorption and a positive shift in calcium balance (+60 mg Ca/day), due primarily to decreased urinary calcium losses. These findings were similar to those observed with hormone replacement therapy.
In the osteoporosis prevention trials, raloxifene therapy resulted in consistent, statistically significant suppression of bone resorption, bone formation and overall bone turnover, 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 quantitative measurements (bone histomorphometry) on animal bones and human iliac crest bone biopsies taken after administration of a fluorochrome substance to label areas of mineralizing bone. The effects of raloxifene on bone histomorphometry were determined by pre-and post-treatment biopsies in a 6-month study of postmenopausal women. Bone in raloxifene-treated women was histologically normal, showing no evidence of mineralization defects, woven bone, or marrow fibrosis. The patterns of change were consistent with reduced bone turnover, although most changes were not statistically significant. In another bone histomorphometry study, postmenopausal women were treated for 6 months with raloxifene at a higher dose (150 mg/day). Bone was also histologically normal, with no woven bone, marrow fibrosis, or mineralization defects.
In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy and preserved bone strength in biomechanical studies. Ovariectomized cynomolgus monkeys were treated with raloxifene for 2 years, equivalent at the bone level to 6 years in humans. The biomechanical properties of bone from the raloxifene-treated monkeys were normal. Histologic examination of bone from rats and monkeys treated with raloxifene showed normal cancellous bone morphology and no evidence of woven bone, marrow fibrosis, or mineralization defects.
The animal and human bone histomorphometric results are consistent with data from studies of radiocalcium kinetics and markers of bone metabolism and demonstrate that raloxifene is a skeletal antiresorptive agent.
Effects on Lipid Metabolism: In numerous epidemiologic studies, estrogen use after menopause is associated with reduced risk of atherosclerotic cardiovascular disease. The cardiovascular protective effects of estrogen are believed to be mediated by its effects on lipids and nonlipid risk factors. In animal studies, the effects of raloxifene on cholesterol metabolism were mediated through the estrogen receptor.
The effects of raloxifene on cardiovascular intermediate endpoints were evaluated in a 6-month study of 390 postmenopausal women. Raloxifene was compared with continuous combined estrogen/progestin (0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate, [HRT]) and placebo (see Table III). Raloxifene decreased serum total and LDL cholesterol without significant effects on serum total HDL cholesterol or triglycerides. Raloxifene significantly increased HDL-2 cholesterol subfraction. In addition, raloxifene significantly decreased serum fibrinogen and lipoprotein (a).
In the osteoporosis prevention studies (N=1 764), 24-month data were consistent with results from the 6-month cardiovascular study. Compared with placebo, raloxifene significantly decreased serum total and LDL cholesterol, but did not increase HDL cholesterol or triglycerides.
Effects on the Uterus: Postmenopausal estrogen deficiency leads to endometrial atrophy. Estrogen replacement therapy is associated with endometrial proliferation and hyperplasia and increased risk of endometrial carcinoma. All forms of hormone replacement therapy are often accompanied by spotting and bleeding. In contrast, raloxifene has no endometrial stimulatory effect and does not induce spotting or bleeding.
In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months (for 24 months) by transvaginal ultrasonography (TVU), a noninvasive method of visualizing the uterus. A total of 2 978 TVU measurements were collected from 831 women in all dose groups. Raloxifene-treated women consistently had endometrial thickness measurements indistinguishable from placebo. Furthermore, there were no differences between the raloxifene and placebo groups with respect to the incidence of reported vaginal bleeding.
In a 6-month study comparing raloxifene to conjugated equine estrogens (0.625 mg/day [ERT]), endpoint endometrial biopsies demonstrated stimulatory effects of ERT which were not observed for raloxifene. All samples from raloxifene-treated women showed nonproliferative endometrium.
A 12-month study of uterine effects compared a higher dose of raloxifene (150 mg/day) with HRT. At baseline, 43 raloxifene-treated women and 37 HRT-treated women had a nonproliferative endometrium. At study completion, endometrium 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.
The postmenopausal endometrium is atrophic due to the lack of endogenous estrogen. Consequently, the estrogen antagonist effects of raloxifene on this tissue could not be demonstrated in the clinical trials. However, raloxifene is a potent estrogen antagonist in the rat uterus, where it completely blocks the stimulatory effects of estrogen. In the absence of estrogen stimulation, raloxifene did not have any stimulatory effects on the endometrium in any animal models tested.
Effects on the Breast: Estrogen replacement therapy and hormone replacement therapy stimulate glandular and stromal components of breast tissue, resulting in symptoms of breast pain and tenderness in some postmenopausal women. In contrast, raloxifene does not stimulate breast tissue. Across all placebo-controlled trials, raloxifene was indistinguishable from placebo with regard to frequency and severity of breast symptoms. Raloxifene was associated with significantly fewer breast symptoms than reported by women receiving estrogens with or without added progestin (see Adverse Effects).
The estrogen antagonist aspects of raloxifene’s SERM profile were examined in a variety of preclinical breast cancer models. Raloxifene inhibited the growth of MCF-7 human breast cancer cells in vitro and of MCF-7 xenograft tumors in mice. In animal models of carcinogen-induced breast cancer (nitrosomethylurea [NMU] and dimethylbenzanthracene [DMBA]), raloxifene decreased tumor burden.
In clinical trials with raloxifene involving 12 802 patients, approximately 8 300 women were exposed to raloxifene for up to 39 months. There was a statistically significant reduction in the frequency of newly diagnosed breast cancers in raloxifene-treated women compared with placebo (see Adverse Effects, Additional Safety Information). These observations are consistent with the preclinical pharmacologic profile of raloxifene (selective estrogen receptor modulator) and support the conclusion that raloxifene has no intrinsic estrogen agonist activity in mammary tissue. The long-term (beyond 39 months) effects of raloxifene on the incidence of breast cancer are not yet known.
Indications And Clinical Uses: For the prevention of osteoporosis in postmenopausal women.
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 build, 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.
Contra-Indications: Women of childbearing potential. Raloxifene therapy during pregnancy may be associated with an increased risk of congenital defects in the fetus.
Raloxifene is contraindicated in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.
Raloxifene is contraindicated in women known to be hypersensitive to raloxifene or other constituents of the tablets.
Manufacturers’ Warnings In Clinical States: Venous Thromboembolic Events: An analysis of raloxifene-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 magnitude of risk is similar to that associated with current use of hormone replacement therapy. Raloxifene should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and raloxifene therapy should be resumed only after the patient is fully ambulatory. The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons.
Premenopausal Use: There is no indication for premenopausal use of raloxifene. Safety of raloxifene 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 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 hepatic insufficiency.
Precautions: General: Concurrent Estrogen Therapy: The concurrent use of raloxifene and systemic estrogen or hormone replacement therapy (ERT or HRT) has not been studied in prospective clinical trials.
Lipid Metabolism: Raloxifene lowers serum total and LDL cholesterol by 6 to 11%, but does not affect serum concentrations of total HDL cholesterol or triglycerides. HDL-2 cholesterol subfraction is increased by raloxifene. These effects should be taken into account in therapeutic decisions for patients who may require therapy for hyperlipidemia. Concurrent use of raloxifene and lipid lowering agents has not been studied.
Endometrium: Raloxifene does not cause endometrial proliferation (see Pharmacology and Adverse Effects). Unexplained uterine bleeding should be investigated as clinically indicated.
Breast: Raloxifene is not associated with breast enlargement, breast pain, or increased risk of breast cancer (see Pharmacology and Adverse Effects). Any unexplained breast abnormality occurring during raloxifene therapy should be investigated.
History of Breast Cancer: Raloxifene has not been studied in women with a prior history of breast cancer.
Use in Men: There is no indication for use of raloxifene in men.
Children: Raloxifene should not be used in pediatric patients.
Information to be Provided to the Patient: For safe and effective use of raloxifene, the physician should inform patients about the following: Patient Immobilization: Raloxifene should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., postsurgical recovery, prolonged bed rest) and raloxifene therapy should be resumed only after the patient is fully ambulatory because of the increased risk of venous thromboembolic events.
Vasodilatation: Raloxifene is not effective in reducing vasodilatation (hot flashes or flushes) associated with estrogen deficiency. In some patients, vasodilatation may occur on beginning raloxifene therapy.
Other Preventive Measures: Patients should be instructed to take supplemental calcium and vitamin D if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or alcohol consumption, if these factors exist.
Drug Interactions: Cholestyramine: Cholestyramine significantly reduces the absorption and enterohepatic cycling of raloxifene and should not be coadministered with raloxifene.
Warfarin: Coadministration of raloxifene and warfarin does not alter the pharmacokinetics of either compound. However, modest decreases in prothrombin time have been observed in single-dose studies. If raloxifene is given concurrently with warfarin, prothrombin time should be monitored.
Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins, but is found at 2 to 5 nM concentration in human plasma. In vitro, raloxifene did not affect the binding of warfarin, phenytoin or tamoxifen. Nevertheless, caution should be used when raloxifene is coadministered with other highly protein-bound drugs.
Laboratory Test Interactions : Raloxifene is not known to interfere with any common laboratory assays (see Adverse Effects for additional laboratory safety information).
Pregnancy: Raloxifene should not be used in women who are or may become pregnant (see Contraindications).
Labor and Delivery: Raloxifene has no recognized use during labor or delivery.
Lactation: Raloxifene should not be used by lactating women (see Contraindications). It is not known whether raloxifene is excreted in human milk.
Adverse Reactions: The safety of raloxifene has been established in Phase 2 and Phase 3 placebo-controlled, estrogen-controlled and HRT-controlled studies. Twelve studies comprise the primary safety database for the prevention indication. The duration of treatment ranged from 2 to 30 months and 2 036 women were exposed to raloxifene. All events were reported irrespective of causality.
Commonly Observed Adverse Events: The most commonly observed treatment-emergent adverse events associated with the use of raloxifene in double-blind, placebo-controlled clinical trials that occurred at an incidence ³2% are shown in Table V. These events occurred in postmenopausal women who took raloxifene for up to 30 months. The differences between raloxifene and placebo treatments were significant at p
Adverse Events Associated with Discontinuation of Therapy: The majority of adverse events occurring during clinical trials have been mild and have not required discontinuation of therapy. Discontinuation of therapy due to any clinical adverse experience occurred in 11.4% of 581 raloxifene-treated women and 12.2% of 584 placebo-treated women.
Adverse Events in Placebo-controlled Clinical Trials: lists adverse events occurring in all placebo-controlled clinical trials with raloxifene at a frequency Â³2% in either group and at rates in raloxifene-treated women numerically greater than in placebo-treated women. Events previously discussed are not included in this table. None of the differences shown in the table were statistically significant and no causal inferences can be made.
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. Approximately 8 300 women have been exposed to raloxifene for up to 39 months.
Endometrium: All cases of endometrial carcinoma are reviewed without knowledge of treatment status (blinded) by an independent Adjudication Review Board. Raloxifene does not increase the risk of endometrial cancer when compared to placebo.
Breast: All cases of breast cancer in women enrolled in clinical trials are reviewed without knowledge of treatment status (blinded) by an independent Adjudication Review Board. A statistically significant 54% reduction (95% confidence interval, 23% to 72% reduction) has been observed in the incidence of newly-diagnosed breast cancer in raloxifene-treated women compared with placebo. The incidence rate of breast cancer was 3.83 per 1 000 subject-years for the women receiving placebo and 1.78 per 1 000 subject-years for those receiving raloxifene. The long-term (beyond 39 months) effects of raloxifene on the incidence of breast cancer are not yet known.
Laboratory Changes: The following changes in analyte concentrations are commonly observed during raloxifene therapy: increased serum HDL-2 cholesterol subfraction and apolipoprotein A1; and reduced serum total cholesterol, LDL cholesterol, fibrinogen, apolipoprotein B and lipoprotein (a). Raloxifene 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.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Incidents of overdose in humans have not been reported. In an 8-week study of 63 postmenopausal women, a dose of raloxifene HCl 600 mg/day was safely tolerated. No mortality was seen after a single oral dose in rats or mice at 5 000 mg/kg or in monkeys at 1 000 mg/kg. There is no specific antidote for raloxifene.
Dosage: The recommended dosage is 1 tablet daily which may be administered any time of day without regard to meals.
Availability And Storage: Each white, elliptical, film-coated tablet, imprinted on one side with the tablet code 4165 in blue ink, contains: raloxifene HCl 60 mg. Nonmedicinal ingredients: anhydrous lactose, crospovidone, FD&C Blue No. 2 aluminum lake, hydroxypropyl methylcellulose, lactose monohydrate, macrogol 400, magnesium stearate, polysorbate 80, povidone and titanium dioxide E171. Blister packages of 28. Store at room temperature, 15 to 30°C.
EVISTA Lilly Raloxifene HCl Selective Estrogen Receptor Modulator