Evista®

Raloxifene HCl

Selective Estrogen Receptor Modulator

Lilly

http://www.lilly.com/

Evista Monograph PDF download here.

 

 

 

 

Pharmacology

Evista (raloxifene hydrochloride) is a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The SERM profile of Evista 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 more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials using a population approach. Pharmacokinetic data were also obtained in conventional clinical pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30%) of most pharmacokinetic parameters.  Table 1 summarizes the pharmacokinetic parameters of raloxifene.

CPS:Evista_t1Click here for Table 1

Table 1: Evista

Summary of Raloxifene Pharmacokinetic Parameters in the Healthy Postmenopausal Woman

 

	Cmaxa  (ng/mL)/(mg/kg)	t½ (h)	AUC0-∞a  (ng·h/mL)/(mg/kg)	CL/F (L/kg·h)	V/F (L/kg)
Single Dose
Mean	0.50	27.7	27.2	44.1	2348
CV (%)	52	10.7 to 273b	44	46	52
Multiple Dose
Mean	1.36	32.5	24.2	47.4	2853
CV (%)	37	15.8 to 86.6b	36	41	56

 

 ^a data normalized based on dose in mg and body weight in kg.

 ^b range of observed half-life.

 

 

Legend:C_max=maximum plasma concentration

t½=half-life

AUC=area under the curve

 CL=clearance

F=bioavailability

V=volume of distribution

CV=coefficient of variation

 

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 HCI with a standardized, high-fat meal increases the absorption of raloxifene slightly, 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 HCI, 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 α 1-acid glycoprotein, but not to sex steroid binding globulin.

Metabolism

Biotransformation and disposition of raloxifene in humans have been determined following oral administration of ¹⁴C-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/kg·h. Increasing doses of raloxifene HCI (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 negligible amounts are excreted unchanged in urine. Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates.

Special Populations

Geriatrics: The pharmacokinetics of raloxifene are independent of age (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 male and female volunteers.

Race: Pharmacokinetic differences due to race have been studied in 1712 women including 97.5% Caucasian, 1.0% Asian, 0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053 women including 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. The influence of race can not be conclusively determined because of the small numbers of non-Caucasians.

Renal Insufficiency: Since negligible amounts of raloxifene are eliminated in urine, a study in patients with renal insufficiency was not conducted. In the osteoporosis treatment and prevention trials, raloxifene and metabolite concentrations were not affected by renal function in women having estimated creatinine clearance as low as 21 mL/min (0.35 mL/s).

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 (10.3 to 34.2 µmol/L). 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 Interactions

Clinically significant drug-drug interactions are discussed in Precautions.

Ampicillin and Other Oral Antimicrobials: 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. In the osteoporosis treatment trial, coadministered oral antimicrobial agents (including amoxicillin, cephalexin, ciprofloxacin, macrolide antibiotics, sulfamethoxazole/trimethoprim and tetracycline) had no effect on plasma raloxifene concentrations.

Corticosteroids: The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose.

Digoxin: Raloxifene has no effect on the pharmacokinetics of digoxin. In the osteoporosis treatment trial, coadministered digoxin had no effect on plasma raloxifene concentration.

Gastrointestinal Medications: Concurrent administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. In the osteoporosis treatment trial, coadministered gastrointestinal medications (including bisacodyl, cisapride, docusate, H₂-antagonists, laxatives, loperamide, omeprazole and psyllium) had no effect on plasma raloxifene concentration.

Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. The influence of co-administered highly protein-bound drugs (including diazepam, gemfibrozil, ibuprofen, naproxen and warfarin) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified. In vitro, raloxifene did not affect the binding of phenytoin, tamoxifen or warfarin.

Highly Glucuronidated Drugs: Raloxifene undergoes extensive first-pass metabolism to glucuronide conjugates. The influence of co-administered highly glucuronidated drugs (including acetaminophen, ketoprofen, morphine and oxazepam) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified.

Other Medications: The influence of concomitant medications on raloxifene plasma concentrations was evaluated in the osteoporosis treatment clinical trial. The 152 most commonly co-administered medications were grouped by pharmacological class based on their therapeutic use. Frequently co-administered drugs included: ACE inhibitors and angiotensin antagonists, alpha agonists and antagonists, anticholinergics, antidepressants, antimicrobials, antipsychotics, benzodiazepines, β -blockers and -agonists, bisphosphonates, calcium channel blockers, diuretics, estrogen preparations, glucocorticoids, guaifenesin, H₁-antagonists, H₂-antagonists and proton pump inhibitors, hypoglycemics, hypolipidemics, iron preparations, muscle relaxants, nitrates, non-benzodiazepine hypnotics, non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, theophylline and thyroid hormone. No clinically relevant effects of the co-administration of any of these agents on raloxifene plasma concentrations were observed.

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 may reduce the risk of coronary artery disease, but it also increases the risk of endometrial carcinoma and possibly breast cancer. The selective estrogen receptor modulator (SERM) profile of Evista includes estrogen agonist effects on bone and lipid metabolism, and estrogen antagonist effects in uterine and breast tissues. Thus, Evista is a first line option for the treatment and 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 two 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, accelerated bone loss and increased risk of fracture. 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 Evista increases BMD to a lesser extent than estrogen, the effects of Evista 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.

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. The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip bone mineral density 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. All women received calcium (500 mg/day) and vitamin D (400 to 600 IU/day).Evista, 60 mg administered once daily, decreased the incidence of one or more vertebral fractures by as much as 55% ( Table 2) and increased BMD compared to an active therapy of calcium plus vitamin D supplemented placebo. Evista reduced the incidence of vertebral fractures whether or not patients had experienced a previous fracture. The decrease in incidence of vertebral fracture was greater than could be accounted for by increase in BMD alone ( Figure 1).

CPS:Evista_t2Click here for Table 2

Table 2: Evista

Effect of Evista on Risk of Vertebral Fractures

 

	Number of Patients			Relative Risk
	Evista	Placebo	(95% Cl)
Patients with no baseline fracturea	n=1401	n=1457
Number of patients with ≥ 1 new vertebral fracture	27	62	0.45 (0.29, 0.71)
Patients with ≥ 1 baseline fracturea	n=858	n=835
Number of patients with ≥ 1 new vertebral fracture	121	169	0.70 (0.56, 0.86)
All randomized patients	n=2557	n=2576
Number of patients with ≥ 1 new clinical (painful) vertebral fracture	47	81	0.59 (0.41, 0.83)

 

 ^a Includes all patients with baseline and at least one follow-up radiograph.

 

 

 

Figure 1:

Evista

Correlation Between Vertebral Fracture Risk and Percent Change in Femoral Neck BMD at 3 yrs

 

Changes in BMD do not fully account for vertebral fracture risk reduction. This figure shows the correlation between vertebral fracture risk and percent change in femoral neck BMD at 3 years based on a logistic regression analysis of the clinical trial data. For any given change in BMD from baseline, Evista-treated patients had a lower risk for vertebral fracture compared to placebo.

 

 

     Retrospective analysis of the patients in the osteoporosis treatment study, demonstrates that there was a statistically significant reduction (p<0.001) in the risk of clinical (symptomatic) vertebral fracture after 12 months of treatment. At 12 months the risk of clinical vertebral fractures was decreased by 68% (95% CI, 0.13-0.79) in postmenopausal women taking Evista 60 mg per day.

     The same osteoporosis treatment study was extended by 12 months to a 4th year during which, patients were permitted the use of concomitant medications, including bisphosphonates, calcitonins and fluorides. The statistically significant reduction in vertebral fractures and increase in BMD seen at 3 years continued into the 4th year extension of the osteoporosis treatment study. The sustained reduction in vertebral fractures is illustrated in  Figure 2, a Kaplan-Meier analysis of time to first vertebral fracture over the 48 months of the study.

 

Figure 2:

Evista

Time To Event For Vertebral Fractures Over 48 Months

 

     Overall osteoporotic fracture risk was significantly reduced with Evista therapy. Over 4 years there was no difference seen in nonvertebral fracture incidence in women treated with raloxifene compared to placebo. At 3 years, the risk of individual nonvertebral fractures versus placebo decreased with increasing exposure to Evista.

     At every time point, the mean percentage change in BMD from baseline for Evista was significantly greater than for placebo at each skeletal site measured ( Table 3).

CPS:Evista_t3Click here for Table 3

Table 3: Evista

Evista (60 mg once daily) Related Increases in BMD for the Osteoporosis Treatment Study Expressed as Mean Percentage Increase Versus Calcium- and Vitamin D-supplemented Placebo^a

 

Site	Time
	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

 

 ^a Intent-to-treat analysis; last observation carried forward.

 

 

Legend:ND=not done (total body and radius BMD were measured only at 24 months).

Note: All BMD increases were statistically significant (p<0.001).

 

     Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred. Such discontinuation was significantly more frequent in the calcium- and vitamin D-supplemented placebo group (3.9%) than in the Evista group (1.1%).

Prevention of Osteoporosis: 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). Evista, 60 mg raloxifene HCI 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 ( Table 4). In contrast, the calcium-supplemented placebo groups lost approximately 1% of BMD over 24 months.

CPS:Evista_t4Click here for Table 4

Table 4: Evista

Evista Increases in BMD For the 3 Osteoporosis Prevention Studies Expressed as Percentage Increase Versus Calcium-Supplemented Placebo at 24 Months

 

Site	Study
	NA %	EU %	INTa  %
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

 

 ^a All women in the study had previously undergone hysterectomy.

 

 

Legend:NA=North American, EU=European, INT=international.

 

     Evista 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, Evista 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.

Assessments of Bone Turnover: In a 31-week radiocalcium kinetics study, Evista 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 both the osteoporosis treatment and prevention trials, Evista 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 36-month and 24-month observation periods, respectively.

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 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 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 Evista on bone histomorphometry were determined by pre-and post-treatment biopsies in a 6-month study of postmenopausal women. Bone in Evista-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 HCI 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 Evista is a skeletal antiresorptive agent.

Effects on Lipid Metabolism

In animal studies, the effects of raloxifene on cholesterol metabolism were mediated through the estrogen receptor.

     The effects of Evista on cardiovascular intermediate endpoints were evaluated in a 6-month study of 390 postmenopausal women. Evista was compared with continuous combined estrogen/progestin (0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate, [HRT]) and placebo ( Table 5). Evista decreased serum total and LDL cholesterol without significant effects on serum total HDL cholesterol or triglycerides. Evista significantly increased HDL-2 cholesterol subfraction. In addition, Evista significantly decreased serum fibrinogen and lipoprotein (a).

CPS:Evista_t5Click here for Table 5

Table 5: Evista

Evista and HRT Effects on Cardiovascular Intermediate Endpoints in a 6-Month Study—Median Percentage Change from Baseline

 

Endpoint	Treatment Group
	Placebo (N=98)  %	Evista (N=95)  %	HRT (N=96)  %
Total Cholesterol	0.9	-6.6	-4.4
LDL Cholesterol	1.0	-10.9	-12.7
HDL Cholesterol	0.9	0.7	10.6
HDL-2 Cholesterol	0.0	15.4	33.3
Fibrinogen	-2.1	-12.2	-2.8
Lipoprotein (a)	3.3	-4.1	-16.3
Triglycerides	-0.3	-4.1	20.0

 

Legend:HRT=continuous combined estrogen/progestin (0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate).

 

     Consistent with results from the 6-month study, in the osteoporosis treatment (36 months) and prevention (24 months) studies Evista significantly decreased serum total and LDL cholesterol, but did not increase HDL cholesterol or triglycerides. In the osteoporosis treatment study, significantly fewer Evista-treated patients required initiation of hypolipidemic therapy compared to placebo.

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, Evista has no endometrial stimulatory effect and does not induce spotting or bleeding.

     In the osteoporosis treatment trial, endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years. Endometrial thickness measurements in Evista-treated women were not different from baseline after 3 years of therapy. Placebo-treated women had a 0.27 mm decrease from baseline in endometrial thickness over 3 years. 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 non-invasive 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 Evista to conjugated equine estrogens (0.625 mg/day [ERT]), endpoint endometrial biopsies demonstrated stimulatory effects of ERT which were not observed for raloxifene ( Table 6). All samples from Evista-treated women showed nonproliferative endometrium.

CPS:Evista_t6Click here for Table 6

Table 6: Evista

Evista and ERT Effects on Endometrial Histology After 6–Months of Therapy

 

Endpoint Biopsy Result	Treatment Group
	Evista (n=10)	ERT (n=8)
Nonproliferative Endometriuma	10	2
Proliferative Tissue	0	4
Simple Hyperplasia	0	2

 

 ^a The term, nonproliferative endometrium, includes endometrial atrophy, surface endometrium and inadequate sample.

 

 

Legend:ERT=conjugated equine estrogens (0.625 mg/day).

 

     A 12-month study of uterine effects compared a higher dose of raloxifene HCI (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 Evista 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, Evista does not stimulate breast tissue. Across all placebo-controlled trials, Evista was indistinguishable from placebo with regard to frequency and severity of breast symptoms. Evista 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 Evista involving 17 151 patients, at least 10 850 women were exposed to raloxifene for up to 58 months. There was a statistically significant reduction in the frequency of newly diagnosed breast cancers in raloxifene-treated women compared with placebo (see Additional Safety Information). These observations are consistent with the preclinical pharmacologic profile of raloxifene (selective estrogen receptor modulator) and support the conclusion that Evista has no intrinsic estrogen agonist activity in mammary tissue. The long-term effectiveness of raloxifene in reducing the risk of breast cancer has not been fully established.

 

Indications

Evista is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

Clinical Usage

     For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal osteoporosis may be diagnosed by history or radiographic documentation of osteoporotic fracture, bone mineral densitometry, or physical signs of vertebral crush fractures (e.g., height loss, dorsal kyphosis). Women with diagnosed postmenopausal osteoporosis should be considered for pharmacologic therapy, in conjunction with education and appropriate lifestyle modifications.

     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, personal history of any fracture after age 40 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. These risk factors may be considered in the decision to use raloxifene for prevention of postmenopausal osteoporosis.

 

Contraindications

Evista is contraindicated in women of childbearing potential. Evista therapy during pregnancy may be associated with an increased risk of congenital defects in the fetus.

     Evista is contraindicated in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.

     Evista is contraindicated in women known to be hypersensitive to raloxifene or other constituents of the tablets.

 

Warnings

Venous Thromboembolic Events (VTE)

In clinical trials, Evista-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism). The risk of VTE is reported infrequently, occuring in 1.44, 3.32 and 3.63 events per 1000 person-years for placebo, raloxifene 60 mg/day and raloxifene 120 mg/day, respectively. Other venous thromboembolic events could also occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with Evista. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk is similar to that associated with use of hormone replacement therapy. 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. 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 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 mg/dL (10.3 to 34.2 µmol/L). 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 Evista and systemic estrogen or hormone replacement therapy (ERT or HRT) has not been studied in prospective clinical trials.

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. HDL-2 cholesterol subfraction is increased by Evista. 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 does not cause endometrial proliferation (see Pharmacology and Adverse Effects). Unexplained uterine bleeding should be investigated as clinically indicated.

Breast: Evista 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 Evista therapy should be investigated.

History of Breast Cancer: Evista has not been studied in women with a prior history of breast cancer.

Cognition and Affect: Evista has not been associated with deterioration of cognitive function or a change in affect. Any such change during Evista use is unlikely to be related to therapy, and should be investigated as clinically indicated.

Use in Men

There is no indication for use of Evista in men.

 

Children

Evista should not be used in pediatric patients.

Geriatrics

In the osteoporosis treatment trial of 7705 postmenopausal women, 4621 women were considered geriatric (greater than 65 years old). Of these, 845 women were greater than 75 years old. Safety and efficacy in older and younger postmenopausal women in the osteoporosis treatment trial appear to be comparable.

Estrogen-induced Hypertriglyceridemia

In a 12 patient, single-arm, open-label study in patients with a history of oral estrogen-induced marked hypertriglyceridemia (generally 5.6 to 39 mmol/L [500 to 3400 mg/dL]), 3 patients had increases of serum triglycerides to >11.3 mmol/L (1000 mg/dL) within 2 weeks after initiation of raloxifene therapy. In 2 of these 3 patients, serum triglyceride levels decreased while raloxifene was continued. Patients with this medical history should have serum triglycerides monitored when taking raloxifene.

Information to Be Provided to the Patient

 For safe and effective use of raloxifene, the physician should inform patients about the following:

Patient Immobilization: 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 because of the increased risk of venous thromboembolic events.

Vasodilatation: Evista is not effective in reducing vasodilatation (hot flashes or flushes) associated with estrogen deficiency. In some patients, vasodilatation may occur on beginning Evista therapy.

Other Osteoporosis Treatment and Prevention Measures: Patients should be instructed to take supplemental calcium and/or 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, an anion exchange resin, significantly reduces the absorption and enterohepatic cycling of raloxifene and should not be coadministered with raloxifene. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect.

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 or other coumarin derivatives, prothrombin time should be monitored.

Laboratory Test Interactions

Evista is not known to interfere with any common laboratory assays (seeAdverse Effects for additional laboratory safety information).

 

Pregnancy

Evista should not be used in women who are or may become pregnant (see Contraindications).

Labor and Delivery: Evista has no recognized use during labor or delivery.

 

Lactation

Evista should not be used by lactating women (see Contraindications). It is not known whether raloxifene is excreted in human milk.

 

Adverse Effects

The safety of raloxifene has been established in Phase 2 and Phase 3 placebo-controlled, estrogen-controlled, and HRT-controlled studies. Twelve studies comprised the primary safety database for the prevention indication, and the safety of raloxifene in the treatment of osteoporosis was assessed in a large (N=7705), multinational, placebo-controlled trial. In the osteoporosis prevention trials, the duration of treatment ranged from 2 to 30 months and 2036 women were exposed to raloxifene. In the osteoporosis treatment trial, 5129 women were exposed to raloxifene (2557 received 60 mg/day and 2572 received 120 mg/day) for 36 months. In the 4^th year, patients were permitted the concomitant use of bisphosphonates, calcitonin and fluorides. All events were reported irrespective of causality.

Commonly Observed Adverse Events: The most commonly observed treatment-emergent adverse events associated with the use of Evista in double-blind, placebo-controlled, osteoporosis treatment and prevention clinical trials that occurred at an incidence ≥ 2% are shown in  Table 7. These events occurred in postmenopausal women who took raloxifene for up to 36 months in the osteoporosis treatment trial and for up to 30 months in the osteoporosis prevention trials. The differences between raloxifene and placebo treatments were significant at p<0.05.

     Vasodilatation events (hot flashes or flushes) were common in placebo-treated women and the frequency was modestly increased in Evista-treated women. The first occurrence of this event was most commonly reported during the first 6 months of treatment and infrequently was reported de novo after that time. At 48 months in the osteoporosis treatment trial, vasodilation was reported in 10.6% of patients on Evista versus 7.1% of placebo patients (p<0.001), and leg cramps were reported in 9.2% of patients on Evista versus 6.0% of placebo patients (p<0.001).

CPS:Evista_t7Click here for Table 7

Table 7: Evista

Adverse Events Associated with Use of Evista (60 mg once daily) Occurring at a Frequency Greater than in Placebo-treated Patients and at an Incidence ≥ 2.0% in Either Group

 

Adverse Event	Treatment		Prevention
	Evista (N=2557) %	Placebo (N=2576) %	Evista (N=581) %	Placebo (N=584) %
Vasodilatation	9.7	6.4	24.6	18.3
Leg Cramps	7.0	3.7	5.9	1.9

 

     At 48 months in the same osteoporosis treatment trial, flu syndrome (16.2% of Evista treated patients versus 14.0% of placebo patients), uterine disorder (endometrial cavity fluid in 12.7% of Evista treated patients versus 9.6% of placebo patients) and peripheral edema (7.1% of Evista treated patients versus 6.1% of placebo patients) were also treatment-emergent adverse events (frequency >2%), which occurred more frequently with patients receiving Evista compared to placebo (p<0.05).

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 10.9% of 2557 Evista-treated women and 8.8% of 2576 placebo-treated women in the osteoporosis treatment trial, and in 11.4% of 581 Evista-treated women and 12.2% of 584 placebo-treated women in the osteoporosis prevention trials.

Adverse Events in Placebo-controlled Clinical Trials:  Table 8 lists adverse events occurring in either the osteoporosis treatment (up to 3 years) or prevention placebo-controlled clinical trials with Evista at a frequency ≥ 2.0% in either group and at rates in Evista-treated women numerically greater than in placebo-treated women. Events previously discussed are not included in this table. Only one of the differences shown in the table (flu syndrome) was statistically significant and no causal inferences can be made for any of these adverse events.

CPS:Evista_t8Click here for Table 8

Table 8: Evista

Adverse Events Occurring in Placebo-controlled Osteoporosis Clinical Trials (up to 36 months) at a Frequency ≥ 2.0% in Either Group and at Rates in Evista-Treated (60 mg once daily) Women Numerically Greater Than in Placebo-treated Women

 

Body System	Treatment		Prevention
	Evista N=2557 %	Placebo N=2576 %	Evista N=581 %	Placebo N=584 %
Body as a Whole
Infection	A	A	15.1	14.6
Flu Syndrome	13.5a	11.4	14.6	13.5
Headache	9.2	8.5	A	A
Chest Pain	A	A	4.0	3.6
Fever	3.9	3.8	3.1	2.6
Cardiovascular
Migraine	A	A	2.4	2.1
Syncope	2.3	2.1	B	B
Varicose Vein	2.2	1.5	B	B
Digestive
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	5.2b	4.4	3.3b	1.9
Musculoskeletal
Arthralgia	15.5	14.0	10.7	10.1
Myalgia	A	A	7.7	6.2
Arthritis	A	A	4.0	3.6
Tendon Disorder	3.6	3.1	A	A
Nervous
Depression	A	A	6.4	6.0
Insomnia	A	A	5.5	4.3
Vertigo	4.1	3.7	A	A
Neuralgia	2.4	1.9	B	B
Hypesthesia	2.1	2.0	B	B
Respiratory
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	6.0	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	2.0	3.1	1.7
Special Senses
Conjunctivitis	2.2	1.7	B	B
Urogenital
Vaginitis	A	A	4.3	3.6
Urinary Tract Infection	A	A	4.0	3.9
Cystitis	4.6	4.5	3.3	3.1
Leukorrhea	A	A	3.3	1.7
Uterine Disorderc ,d	2.5	1.8	A	A
Endometrial Disorderc	B	B	3.1	1.9
Vaginal Hemorrhage	2.5	2.4	A	A
Urinary Tract Disorder	2.5	2.1	A	A

 

 ^a Significantly (p<0.05) different from placebo.

 ^b Significant dose trends at p<0.05.

 ^c Treatment-emergent uterine-related adverse event, including only patients with an intact uterus: Treatment Trial: Evista, n=1948, Placebo, n=1999; Prevention Trials: Evista, n=354; Placebo, n=364.

 ^d Actual terms most frequently referred to endometrial fluid.

 

Legend:A=Placebo incidence greater than or equal to Evista incidence.B=Less than 2% incidence and more frequent with Evista.

 

     The incidence trend of treatment-emergent adverse events (frequency ≥ 2%) after year 4 of the osteoporosis treatment trial were generally similar to the 1 to 3 year results presented in  Table 8. However,  Table 9 details the treatment-emergent adverse events where the relative incidences changed between raloxifene treated patients and placebo patients (e.g., reversed). Please note that in the final (4^th) year of the study, patients were permitted the concomitant use of bisphosphonates, fluorides and calcitonins.

CPS:Evista_t9Click here for Table 9

Table 9: Evista

Changes in Adverse Events from the 3rd Year to the 4th Year Occurring in a Placebo-controlled Osteoporosis Treatment Clinical Trial at a Frequency ≥ 2.0% in Either Evista-treated (60 mg once daily) Women or Placebo-treated Women at 48 Months

 

Body Systems	4th Year Treatment		1st to 3rd Year Incidence Trend (from  Table 8)
	Evista  N=2557  %	Placebo  N=2576 %
Body as a Whole
Infection	18.2	18.0	A
Chest Pain	8.3	8.0	A
Fever	A	A	C
Cardiovascular
Syncope	A	A	C
Digestive
Gastroenteritis	2.1	2.0	B
Metabolic and Nutritional
Weight Gain	3.5	3.4	A
Nervous
Vertigo	A	A	C
Hypesthesia	A	A	C
Respiratory
Rhinitis	A	A	C
Pharyngitis	A	A	C

 

Only those adverse events that changed incidence trend from the 3^rd to the 4^th year are listed.

Legend:A=Placebo incidence greater than or equal to Evista incidence.

B=Less than 2% incidence and more frequent with Evista.

C=Evista incidence greater than placebo.

 

Comparison of Evista and Hormone Replacement Therapy Adverse Events: Evista was compared with estrogen-progestin replacement therapy (HRT) in 3 clinical trials for prevention of osteoporosis.  Table 10 shows adverse events occurring at an incidence ≥ 2.0% in any group.

CPS:Evista_t10Click here for Table 10

Table 10: Evista

Adverse Events Reported In Osteoporosis Prevention Clinical Trials with Evista (60 mg once daily) and Continuous Combined or Cyclic Estrogen Plus Progestin (HRT) at an Incidence ≥ 2.0% in Any Treatment Group

 

Adverse Event	Evista (N=317) %	HRT-Continuous Combined  (N=96) %	HRT-Cyclic  (N=219) %
Urogenital
Breast Pain	4.4	37.5a	29.7a
Vaginal Bleedingc	6.2	64.2a	88.5a
Digestive
Flatulence	1.6	12.5a	6.4a
Cardiovascular
Vasodilatation	28.7b	3.1	5.9
Body as a Whole
Infection	11.0b	0	6.8
Abdominal Pain	6.6	10.4a	18.7a
Chest Pain	2.8b	0	0.5

 

 ^a Significantly greater in specific HRT group than Evista (p<0.05).

 ^b Significantly greater in Evista than in HRT (p<0.05).

 ^c Treatment-emergent uterine-related adverse events, excluding patients who had a hysterectomy. (Evista, n=290; HRT-Continuous Combined, n=67; HRT-Cyclic, n=217).

 

 

Legend:Continuous Combined HRT = 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate.

Cyclic HRT = 0.625 mg conjugated equine estrogen for 28 days with concomitant 5 mg medroxyprogesterone acetate or 0.15 mg norgestrel on Days 1 through 14 or 17 through 28.

 

Additional Safety Information

Incidences of estrogen-dependent carcinoma of the endometrium and breast are being evaluated across all completed and ongoing clinical trials involving 17 151 patients. At least 10 850 women have been exposed to raloxifene for up to 58 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 56% reduction (95% confidence interval, 31% to 73% 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 3.97 per 1000 subject-years for the women receiving placebo and 1.65 per 1000 subject-years for those receiving raloxifene. The long-term effectiveness of raloxifene in reducing the risk of breast cancer has not been fully established.

     In a large 3 year randomized, placebo-controlled, multicentred osteoporosis treatment trial that was extended to a 4^th year, during which study patients were permitted to take concomitant medications such as bisphosphonates, calcitonin and fluorides in the 4^th year, raloxifene treatment compared to placebo reduced the risk of breast cancer.

     After 3 years of treatment, considering those cases which have been adjudicated by the Adjudication Review Board (ARB), raloxifene reduced the risk of all breast cancers by 65% (RR 0.35, 95% CI 0.21-0.58). There was a 76% reduction in the rate of all invasive breast cancers (RR 0.24, 95% CI, 0.13-0.44), a 83% reduction in the rate of all estrogen receptor (ER)-positive breast cancer (RR 0.17, 95% CI 0.08-0.35), and a 90% reduction in the rate of all invasive, ER-positive breast cancer (RR 0.10, 95% CI 0.04-0.24). All of these reductions in risk in the pooled raloxifene group (both 60 and 120 mg doses) compared to placebo were statistically significant. The relative risk of ER-negative breast cancers was not statistically significantly different from 1.0. The relative risk of breast cancer with unknown ER status was also not statistically significantly different from 1.0.

     After 4 years of treatment, raloxifene compared to placebo reduced the incidence of all breast cancers, regardless of invasiveness by 62% (RR 0.38; 95% CI, 0.24-0.58). Regarding invasive breast cancer, there was a 72% reduction in the relative risk (RR 0.28; 95% CI, 0.17-0.46) compared to placebo. After 4 years, the incidence rate of breast cancer was 5.3 per 1000 subject-years and 1.9 per 1000 subject -years, for the placebo and raloxifene treatment groups respectively. This trend for reduced incidence of breast cancer was observed regardless of serum estradiol levels, though patients with higher levels of estradiol had the greatest reductions in absolute risk of breast cancer, compared to placebo.

     In a 5-year, multicentre, double-blind, randomized, placebo-controlled osteoporosis prevention study in 619 healthy postmenopausal women who had undergone hysterectomy, the mean breast density after 2 years was significantly greater in patients receiving estrogen compared to those patients receiving placebo or raloxifene hydrochloride (p<0.01). The mean breast density from baseline to 2 years increased in women taking estrogen (+1.2%), but decreased significantly in women taking placebo (− 1.3%), raloxifene 60 mg/day (− 1.5%) or raloxifene 150 mg/day (− 1.7%). Increased breast density is associated with decreased sensitivity and specificity of mammograms.

Ovary: Evista does not increase the risk of ovarian carcinoma.

Laboratory Changes: The following changes in analyte concentrations are commonly observed during Evista therapy: increased serum HDL-2 cholesterol subfraction and 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.

Glycemic Control: Diabetes mellitus was reported more frequently as an adverse event among Evista-treated patients (1.2%) compared with placebo-treated patients (0.5%) in the osteoporosis treatment trial. However, there were no differences between the raloxifene and placebo groups in either fasting glucose or hemoglobin A_1c (objective measures of glycemic control) in the osteoporosis treatment trial. The diabetes mellitus adverse event finding may have been due to the lower prevalence of diabetes among patients assigned to placebo.

 

Cardiovascular

Raloxifene has been shown in a double-blind, randomized, placebo-controlled, 6-month trial in 390 postmenopausal women to have no significant effect on C-reactive protein, in contrast to continuous combined hormone replacement therapy, which significantly increased C-reactive protein levels.

     C-reactive protein is an independent risk factor for cardiovascular disease; however it remains to be determined how the effects on C-reactive protein influence cardiovascular outcomes in postmenopausal women.

     Results from a 6-month placebo-controlled clinical trial involving 390 postmenopausal women receiving hormone replacement therapy (HRT) or Evista or placebo, demonstrated that Evista (60 mg/day) and HRT had comparable effects on lowering non HDL cholesterol and apo-B/apo-A1 ratio, particularly in women with hypercholsterolemia. Both non-HDL cholesterol and apo-B/apo-A1 are clinical markers of serum atherogenicity.

     Analysis of 3 year data from 2 double-blind, randomized, placebo-controlled trials involving a total of 1145 healthy postmenopausal women assigned to one of four treatment groups, placebo, raloxifene at doses of 30 mg/day, 60 mg/day or 150 mg/day, showed that raloxifene treatment of 60 mg/day significantly decreased serum and total LDL-C compared to placebo (p<0.001) and baseline (p<0.001). In the same patient population, HDL-C and triglyceride concentrations remained unchanged from baseline after 3 years of raloxifene treatment for all doses.

     In a large 3-year randomized, placebo-controlled, multicentred osteoporosis treatment trial that was extended to a 4^th year, there were no significant differences between treatment groups in the overall cohort in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/day of raloxifene, and 94 (3.7%) with 120 mg/day raloxifene. Relative risks (RRs) were 0.86 (95% CI 0.64-1.15) and 0.98 (95% CI 0.74-1.30) for 60 mg/day and 120 mg/day of raloxifene respectively. Among the subset of 1035 women with increased baseline CV risk, those assigned to raloxifene had a significantly lower risk of CV events compared to placebo (RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups).

 

Central Nervous System

In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, cognitive function was assessed as a secondary outcome in 7705 postmenopausal women with osteoporosis. Treatment with raloxifene at 60 mg/day or 120 mg/day for a 3 year period did not affect overall cognitive scores compared to placebo. In the same study, including a 1-year extension during which concomitant medications (bisphosphonates, calcitonins and fluorides) were permitted, neuropsychomotor tests showed no statistically significant differences between placebo and treatment groups for the 4 year period.

 

Overdose

 

     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 5000 mg/kg or in monkeys at 1000 mg/kg.

 

 

Teatment

There is no specific antidote for raloxifene.

 

Dosage

The recommended dosage is one 60 mg Evista tablet daily which may be administered any time of day without regard to meals.

 

Supplied

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.<PATIENTINFO NAME="CPS:BLUE_Evista-IFP">